Processes for the preparation of isoindole compounds and isotopologues thereof

ABSTRACT

Processes for the preparation of certain isoindole compounds, and isotopologues thereof, are provided. In some embodiments, the processes comprise catalytic asymmetrical hydrogenation with hydrogen gas or deuterium gas in a solvent containing exchangeable proton or deuterium for proton-deuterium exchange.

This application is a divisional application of U.S. application Ser.No. 14/026,794, filed on Sep. 13, 2013, which claims priority to U.S.Provisional Application No. 61/701,424, filed Sep. 14, 2012, theentirety of each of which is incorporated herein by reference.

1. FIELD

Provided herein are processes for the preparation of certain isoindolecompounds, and isotopologues thereof, which are useful for treating,preventing, or managing diseases and conditions including, but notlimited to, inflammatory diseases, autoimmune diseases, and cancers.

2. BACKGROUND

Tumor necrosis factor alpha, (TNF-α) is a cytokine that is releasedprimarily by mononuclear phagocytes in response to immunostimulators.TNF-α is capable of enhancing most cellular processes, such asdifferentiation, recruitment, proliferation, and proteolyticdegradation. At low levels, TNF-α confers protection against infectiveagents, tumors, and tissue damage. But TNF-α also has a role in manydiseases. When administered to mammals or humans, TNF-α causes oraggravates inflammation, fever, cardiovascular effects, hemorrhage,coagulation, and acute phase responses similar to those seen duringacute infections and shock states. Enhanced or unregulated TNF-αproduction has been implicated in a number of diseases and medicalconditions, for example, cancers, such as solid tumors and blood-borntumors; heart disease, such as congestive heart failure; and viral,genetic, inflammatory, allergic, and autoimmune diseases.

Adenosine 3′,5′-cyclic monophosphate (cAMP) also plays a role in manydiseases and conditions, such as but not limited to asthma andinflammation, and other conditions (Lowe and Cheng, Drugs of the Future,17(9), 799-807, 1992). It has been shown that the elevation of cAMP ininflammatory leukocytes inhibits their activation and the subsequentrelease of inflammatory mediators, including TNF-α and NF-κB. Increasedlevels of cAMP also leads to the relaxation of airway smooth muscle.

It is believed that the primary cellular mechanism for the inactivationof cAMP is the breakdown of cAMP by a family of isoenzymes referred toas cyclic nucleotide phosphodiesterases (PDE) (Beavo and Reitsnyder,Trends in Pharm., 11, 150-155, 1990). There are eleven known PDEfamilies. It is recognized, for example, that the inhibition of PDE typeIV is particularly effective in both the inhibition of inflammatorymediator release and the relaxation of airway smooth muscle (Verghese,et al., Journal of Pharmacology and Experimental Therapeutics, 272(3),1313-1320, 1995). Thus, compounds that inhibit PDE4 (PDE IV)specifically, may inhibit inflammation and aid the relaxation of airwaysmooth muscle with a minimum of unwanted side effects, such ascardiovascular or anti-platelet effects. Currently used PDE4 inhibitorslack the selective action at acceptable therapeutic doses.

Cancer is a particularly devastating disease, and increases in bloodTNF-α levels are implicated in the risk of and the spreading of cancer.Normally, in healthy subjects, cancer cells fail to survive in thecirculatory system, one of the reasons being that the lining of bloodvessels acts as a barrier to tumor-cell extravasation. But increasedlevels of cytokines have been shown to substantially increase theadhesion of cancer cells to endothelium in vitro. One explanation isthat cytokines, such as TNF-α, stimulate the biosynthesis and expressionof a cell surface receptors called ELAM-1 (endothelial leukocyteadhesion molecule). ELAM-1 is a member of a family of calcium-dependentcell adhesion receptors, known as LEC-CAMs, which includes LECAM-1 andGMP-140. During an inflammatory response, ELAM-1 on endothelial cellsfunctions as a “homing receptor” for leukocytes. Recently, ELAM-1 onendothelial cells was shown to mediate the increased adhesion of coloncancer cells to endothelium treated with cytokines (Rice et al., 1989,Science 246:1303-1306).

Inflammatory diseases such as arthritis, related arthritic conditions(e.g., osteoarthritis and rheumatoid arthritis), inflammatory boweldisease (e.g., Crohn's disease and ulcerative colitis), sepsis,psoriasis, atopic dermatitis, contact dermatitis, and chronicobstructive pulmonary disease, chronic inflammatory pulmonary diseasesare also prevalent and problematic ailments. TNF-α plays a central rolein the inflammatory response and the administration of their antagonistsblock chronic and acute responses in animal models of inflammatorydisease.

Enhanced or unregulated TNF-α production has been implicated in viral,genetic, inflammatory, allergic, and autoimmune diseases. Examples ofsuch diseases include but are not limited to: HIV; hepatitis; adultrespiratory distress syndrome; bone-resorption diseases; chronicobstructive pulmonary diseases; chronic pulmonary inflammatory diseases;asthma, dermatitis; cystic fibrosis; septic shock; sepsis; endotoxicshock; hemodynamic shock; sepsis syndrome; post ischemic reperfusioninjury; meningitis; psoriasis; fibrotic disease; cachexia; graftrejection; auto-immune disease; rheumatoid spondylitis; arthriticconditions, such as rheumatoid arthritis and osteoarthritis;osteoporosis; Crohn's disease; ulcerative colitis; inflammatory-boweldisease; multiple sclerosis; systemic lupus erythrematosus; ENL inleprosy; radiation damage; asthma; and hyperoxic alveolar injury. Traceyet al., 1987, Nature 330:662-664 and Hinshaw et al., 1990, Circ. Shock30:279-292 (endotoxic shock); Dezube et al., 1990, Lancet, 335:662(cachexia); Millar et al., 1989, Lancet 2:712-714 and Ferrai-Balivieraet al., 1989, Arch. Surg. 124:1400-1405 (adult respiratory distresssyndrome); Bertolini et al., 1986, Nature 319:516-518, Johnson et al.,1989, Endocrinology 124:1424-1427, Holler et al., 1990, Blood75:1011-1016, and Grau et al., 1989, N. Engl. J. Med. 320:1586-1591(bone resorption diseases); Pignet et al., 1990, Nature, 344:245-247,Bissonnette et al., 1989, Inflammation 13:329-339 and Baughman et al.,1990, J. Lab. Clin. Med. 115:36-42 (chronic pulmonary inflammatorydiseases); Elliot et al., 1995, Int. J. Pharmac. 17:141-145 (rheumatoidarthritis); von Dullemen et al., 1995, Gastroenterology, 109:129-135(Crohn's disease); Duh et al., 1989, Proc. Nat. Acad. Sci. 86:5974-5978,Poll et al., 1990, Proc. Nat. Acad. Sci. 87:782-785, Monto et al., 1990,Blood 79:2670, Clouse et al., 1989, J. Immunol. 142, 431-438, Poll etal., 1992, AIDS Res. Hum. Retrovirus, 191-197, Poli et al. 1990, Proc.Natl. Acad. Sci. 87:782-784, Folks et al., 1989, PNAS 86:2365-2368 (HIVand opportunistic infections resulting from HIV).

Thus, compounds and compositions that can block the activity or inhibitthe production of PDE4 or certain cytokines, including TNF-α, may bebeneficial as therapeutics. Many small-molecule inhibitors havedemonstrated an ability to treat or prevent inflammatory diseasesimplicated by PDE4 or TNF-α (for a review, see Lowe, 1998 Exp. Opin.Ther. Patents 8:1309-1332).

Certain isoindoline compounds, including(S)—N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamideand(S)—N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-3-oxoisoindolin-4-yl)cyclopropanecarboxamide,have been reported to be capable of controlling angiogenesis orinhibiting the production of certain cytokines, including TNF-α, anduseful in the treatment and prevention of various diseases andconditions. See, e.g., U.S. Pat. Nos. 7,427,638 and 6,667,316,respectively, which are incorporated herein by reference in theirentireties.

Processes for the preparation of isotopologues of isoindoline compounds,including(S)—N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamideand(S)—N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-3-oxoisoindolin-4-yl)cyclopropanecarboxamide,have been reported in International Application Publication No.WO2012/097116, which is incorporated herein by reference in itsentirety.

For example,(S)—N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamideenriched with deuterium at its chiral center can be prepared by reacting(S)-aminosulfone 1 with intermediate 2. (S)-aminosulfone 1 can beprepared by resolution of racemic aminosulfone 3 with N—Ac-L-Leu.Racemic aminosulfone 3 can be prepared by reacting3-ethoxy-4-methoxybenzonitrile 4 with LiCH₂SO₂CH₃, followed by reductionwith NaBD₄ and borate hydrolysis.

A need exists as to more efficient (e.g., without the need of chiralresolution) processes for the preparation of enantiomerically enrichedor enantiomerically pure isoindole compounds and their isotopologues. Aneed also exists as to processes for the preparation of isotopologues ofisoindole compounds, in which the methylene group adjacent to the chiralcenter is also enriched with isotopes such as deuterium.

3. SUMMARY

Provided herein are processes for the preparation of isoindolecompounds, or isotopologues thereof. In one embodiment, provided hereinare processes for the preparation of enantiomerically enriched orenantiomerically pure isoindole compounds, or isotopologues thereof,comprising a step of catalytic asymmetrical hydrogenation with hydrogengas or deuterium gas in a solvent containing exchangeable proton ordeuterium for proton-deuterium exchange.

In one embodiment, provided herein is a process for the preparation ofan enantiomerically enriched or enantiomerically pure compound ofFormula (I):

or a salt, solvate including a hydrate, stereoisomer, isotopologue, orpolymorph thereof, wherein:

-   -   R¹ and R² are each independently hydrogen, halogen, substituted        or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted        (C₁-C₆)alkoxy, (C₃-C₁₈)cycloalkyl, (C₃-C₆)cycloalkoxy, cyano,        —CF₃, (C₃-C₁₈)cycloalkyl-(C₁-C₆)alkoxy, or an isotopologue        thereof;    -   R³ is (C₁-C₆)alkyl, or an isotopologue thereof    -   R is (C₁-C₃)alkyl, (C₃-C₆)cycloalkyl, or an isotopologue thereof    -   Z is C═O, methylene, or an isotopologue thereof and    -   Y¹, Y², and Y³ are independently hydrogen or deuterium;        comprising the step of    -   (a) reducing an enamine of Formula (II):

or a salt or isotopologue thereof, via hydrogenation with hydrogen gasor deuterium gas, in a solvent, and in the presence of (1) a metalcatalyst and a chiral ligand or (2) a chiral metal catalyst/ligandcomplex to form an enantiomerically enriched or enantiomerically pureaminosulfone of Formula (III):

or a salt or isotopologue thereof.

Also provided herein is a process for the preparation of anenantiomerically enriched or enantiomerically pure aminosulfone compoundof Formula (III):

or a salt, solvate including a hydrate, stereoisomer, isotopologue, orpolymorph thereof, wherein:

-   -   R¹ and R² are each independently hydrogen, halogen, substituted        or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted        (C₁-C₆)alkoxy, (C₃-C₁₈)cycloalkyl, (C₃-C₆)cycloalkoxy, cyano,        —CF₃, (C₃-C₁₈)cycloalkyl-(C₁-C₆)alkoxy, or an isotopologue        thereof;    -   R³ is (C₁-C₆)alkyl, or an isotopologue thereof and    -   Y¹, Y², and Y³ are independently hydrogen or deuterium;    -   wherein not all of Y¹, Y², and Y³ are hydrogen;        comprising the step of    -   (a) reducing an enamine of Formula (II):

or a salt or isotopologue thereof, via hydrogenation with hydrogen gasor deuterium gas, in a solvent, and in the presence of (1) a metalcatalyst and a chiral ligand or (2) a chiral metal catalyst/ligandcomplex to form an enantiomerically enriched or enantiomerically pureaminosulfone of Formula (III), or a salt or isotopologue thereof,wherein deuterium gas or a solvent containing exchangeable deuterium forproton-deuterium exchange or both is used.

4. DETAILED DESCRIPTION 4.1 Definitions

As used herein, and unless otherwise indicated, the term “isotopiccomposition” refers to the amount of each isotope present for a givenatom, and “natural isotopic composition” refers to the naturallyoccurring isotopic composition or abundance for a given atom. Atomscontaining their natural isotopic composition may also be referred toherein as “non-enriched” atoms. Unless otherwise designated, the atomsof the compounds recited herein are meant to represent any stableisotope of that atom. For example, unless otherwise stated, when aposition is designated specifically as “H” or “hydrogen,” the positionis understood to have hydrogen at its natural isotopic composition.

As used herein, and unless otherwise indicated, the term “isotopicallyenriched” refers to an atom having an isotopic composition other thanthe natural isotopic composition of that atom. “Isotopically enriched”may also refer to a compound containing at least one atom having anisotopic composition other than the natural isotopic composition of thatatom. As used herein, an “isotopologue” is an isotopically enrichedcompound.

As used herein, and unless otherwise indicated, the term “isotopicenrichment” refers to the percentage of incorporation of an amount of aspecific isotope at a given atom in a molecule in the place of thatatom's natural isotopic composition. For example, deuterium enrichmentof 1% at a given position means that 1% of the molecules in a givensample contain deuterium at the specified position. Because thenaturally occurring distribution of deuterium is about 0.0156%,deuterium enrichment at any position in a compound synthesized usingnon-enriched starting materials is about 0.0156%.

As used herein, and unless otherwise indicated, the term “isotopicenrichment factor” refers to the ratio between the isotopic compositionand the natural isotopic composition of a specified isotope.

With regard to the compounds provided herein, when a particular atomicposition is designated as having deuterium or “D,” it is understood thatthe abundance of deuterium at that position is substantially greaterthan the natural abundance of deuterium, which is about 0.015%. Aposition designated as having deuterium typically has a minimum isotopicenrichment factor of, in particular embodiments, at least 1000 (15%deuterium incorporation), at least 2000 (30% deuterium incorporation),at least 3000 (45% deuterium incorporation), at least 3500 (52.5%deuterium incorporation), at least 4000 (60% deuterium incorporation),at least 4500 (67.5% deuterium incorporation), at least 5000 (75%deuterium incorporation), at least 5500 (82.5% deuterium incorporation),at least 6000 (90% deuterium incorporation), at least 6333.3 (95%deuterium incorporation), at least 6466.7 (97% deuterium incorporation),at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5%deuterium incorporation) at each designated deuterium atom.

The isotopic enrichment and isotopic enrichment factor of the compoundsprovided herein can be determined using conventional analytical methodsknown to one of ordinary skill in the art, including mass spectrometryand nuclear magnetic resonance spectroscopy.

As used herein and unless otherwise indicated, the term “process(es)”provided herein refers to the methods disclosed herein which are usefulfor preparing a compound provided herein. Modifications to the methodsdisclosed herein (e.g., starting materials, reagents, protecting groups,solvents, temperatures, reaction times, purification) are alsoencompassed by the present disclosure.

As used herein, and unless otherwise indicated, the term “adding,”“reacting,” “treating,” or the like means contacting one reactant,reagent, solvent, catalyst, reactive group or the like with anotherreactant, reagent, solvent, catalyst, reactive group or the like.Reactants, reagents, solvents, catalysts, reactive groups or the likecan be added individually, simultaneously or separately and can be addedin any order. They can be added in the presence or absence of heat andcan optionally be added under an inert atmosphere. “Reacting” can referto in situ formation or intramolecular reaction where the reactivegroups are in the same molecule.

As used herein, and unless otherwise indicated, a reaction that is“substantially complete” or is driven to “substantial completion” meansthat the reaction contains more than about 80% by percent yield, in oneembodiment more than about 90% by percent yield, in another embodimentmore than about 95% by percent yield, and in another embodiment morethan about 97% by percent yield of the desired product.

As used herein, and unless otherwise indicated, the term “salt”includes, but is not limited to, salts of acidic or basic groups thatmay be present in the compounds disclosed herein. Compounds that arebasic in nature are capable of forming a wide variety of salts withvarious inorganic and organic acids. The acids that may be used toprepare salts of such basic compounds are those that form saltscomprising anions including, but not limited to, acetate,benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calciumedetate, camsylate, carbonate, chloride, bromide, iodide, citrate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydroxynaphthoate, isethionate, lactate, lactobionate,malate, maleate, mandelate, mesylate, methylsulfate, muscate, napsylate,nitrate, panthothenate, phosphate/diphosphate, polygalacturonate,salicylate, stearate, succinate, sulfate, tannate, tartrate, teoclate,triethiodide, and pamoate. Compounds that include an amino group alsocan form salts with various amino acids, in addition to the acidsmentioned above. Compounds that are acidic in nature are capable offorming base salts with various cations. Non-limiting examples of suchsalts include alkali metal or alkaline earth metal salts and, in someembodiments, calcium, magnesium, sodium, lithium, zinc, potassium, andiron salts. Compounds that are acidic in nature are also capable offorming base salts with compounds that include an amino group.

As used herein, and unless otherwise indicated, the term “hydrate” meansa compound or a salt thereof, that further includes a stoichiometric ornon-stoichiometric amount of water bound by non-covalent intermolecularforces.

As used herein, and unless otherwise indicated, the term “solvate” meansa solvate formed from the association of one or more solvent moleculesto a compound. The term “solvate” includes hydrates (e.g., mono-hydrate,dihydrate, trihydrate, tetrahydrate, and the like).

As used herein, and unless otherwise indicated, the term “polymorph”means solid crystalline forms of a compound or complex thereof.Different polymorphs of the same compound can exhibit differentphysical, chemical and/or spectroscopic properties.

As used herein, and unless otherwise indicated, the term “halo”,“halogen”, or the like means —F, —Cl, —Br, or —I.

As used herein, and unless otherwise indicated, the term “alkyl” means asaturated, monovalent, unbranched or branched hydrocarbon chain.Examples of alkyl groups include, but are not limited to, (C₁-C₆)alkylgroups, such as methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl,2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl,2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl,2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl,and hexyl. Longer alkyl groups include heptyl, octyl, nonyl and decylgroups. An alkyl group can be unsubstituted or substituted with one ormore suitable substituents. The alkyl groups may also be isotopologuesof the natural abundance alkyl groups by being enriched in isotopes ofcarbon and/or hydrogen (i.e., deuterium or tritium).

As used herein, and unless otherwise indicated, the term “alkoxy” meansan alkyl group that is linked to another group via an oxygen atom (i.e.,—O-alkyl). An alkoxy group can be unsubstituted or substituted with oneor more suitable substituents. Examples of alkoxy groups include, butare not limited to, (C₁-C₆)alkoxy groups, such as —O-methyl, —O-ethyl,—O-propyl, —O-isopropyl, —O-2-methyl-1-propyl, —O-2-methyl-2-propyl,—O-2-methyl-1-butyl, —O-3-methyl-1-butyl, —O-2-methyl-3-butyl,—O-2,2-dimethyl-1-propyl, —O-2-methyl-1-pentyl, 3-O-methyl-1-pentyl,—O-4-methyl-1-pentyl, —O-2-methyl-2-pentyl, —O-3-methyl-2-pentyl,—O-4-methyl-2-pentyl, —O-2,2-dimethyl-1-butyl, —O-3,3-dimethyl-1-butyl,—O-2-ethyl-1-butyl, —O-butyl, —O-isobutyl, —O-t-butyl, —O-pentyl,—O-isopentyl, —O-neopentyl and —O-hexyl. The alkoxy groups may also beisotopologues of the natural abundance alkoxy groups by being enrichedin isotopes of carbon, oxygen and/or hydrogen (i.e., deuterium ortritium).

As used herein, and unless otherwise indicated, the term “alcohol” meansany compound substituted with an —OH group. The alcohol group may alsobe isotopologues of the natural abundance alcohol groups by beingenriched in isotopes of oxygen and/or hydrogen (i.e., deuterium ortritium).

As used herein, and unless otherwise indicated, the term “amino” or“amino group” means a monovalent group of the formula —NH₂, —NH(alkyl),—NH(aryl), —N(alkyl)₂, —N(aryl)₂ or —N(alkyl)(aryl). The amino groupsmay also be isotopologues of the natural abundance amino groups by beingenriched in isotopes of carbon, nitrogen and/or hydrogen (i.e.,deuterium or tritium).

Unless otherwise indicated, the compounds provided herein, includingintermediates useful for the preparation of the compounds providedherein, which contain reactive functional groups (such as, withoutlimitation, carboxy, hydroxy, and amino moieties) also include protectedderivatives thereof “Protected derivatives” are those compounds in whicha reactive site or sites are blocked with one or more protecting groups(also known as blocking groups). Suitable protecting groups for carboxymoieties include benzyl, t-butyl, and the like as well as isotopologuesof the like. Suitable protecting groups for amino and amido groupsinclude acetyl, trifluoroacetyl, t-butyloxycarbonyl, benzyloxycarbonyl,and the like. Suitable protecting groups for hydroxy include benzyl andthe like. Other suitable protecting groups are well known to those ofordinary skill in the art. The choice and use of protecting groups andthe reaction conditions to install and remove protecting groups aredescribed in T. W. Green, Protective Groups in Organic Synthesis (ThirdEd., Wiley, New York, 1999), which is incorporated herein by referencein its entirety.

As used herein, and unless otherwise indicated, acronyms or symbols forgroups or reagents have the following definition: HPLC=high performanceliquid chromatography; TFA=trifluoroacetic acid;TFE=2,2,2-trifluoroethanol, THF=tetrahydrofuran; CH₃CN=acetonitrile;HOAc=acetic acid; DCM=dichloromethane.

As used herein, and unless otherwise indicated, the term “substituted”or “substitution,” when used to describe a chemical structure or moiety,refers to a derivative of that structure or moiety wherein one or moreof its hydrogen atoms is replaced with a substituent such as, but notlimited to: alkyl, alkenyl, alkynyl, and cycloalkyl; alkoxyalkyl; aroyl;deuterium, halo; haloalkyl (e.g., trifluoromethyl); heterocycloalkyl;haloalkoxy (e.g., trifluoromethoxy); hydroxy; alkoxy; cycloalkyloxy;heterocyclooxy; oxo; alkanoyl; aryl; heteroaryl (e.g., indolyl,imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, andpyrimidyl); arylalkyl; alkylaryl; heteroaryl; heteroarylalkyl;alkylheteroaryl; heterocyclo; heterocycloalkyl-alkyl; aryloxy,alkanoyloxy; amino; alkylamino; arylamino; arylalkylamino;cycloalkylamino; heterocycloamino; mono- and di-substituted amino;alkanoylamino; aroylamino; aralkanoylamino; aminoalkyl; carbamyl (e.g.,CONH₂); substituted carbamyl (e.g., CONH-alkyl, CONH-aryl,CONH-arylalkyl or instances where there are two substituents on thenitrogen); carbonyl; alkoxycarbonyl; carboxy; cyano; ester; ether;guanidino; nitro; sulfonyl; alkylsulfonyl; arylsulfonyl;arylalkylsulfonyl; sulfonamido (e.g., SO₂NH₂); substituted sulfonamido;thiol; alkylthio; arylthio; arylalkylthio; cycloalkylthio;heterocyclothio; alkylthiono; arylthiono; and arylalkylthiono. In someembodiments, a substituent itself may be substituted with one or morechemical moieties such as, but not limited to, those described herein.

As used herein, and unless otherwise indicated, the term “about” is usedto specify that the values given are approximate. For example, the term“about,” where it is used in connection with reaction temperatures,denotes that the temperature deviations within 30%, 25%, 20%, 15%, 10%,or 5% are encompassed by the temperature indicated. Similarly, the term“about,” where it is used in connection with reaction time, denotes thatthe time period deviations within 30%, 25%, 20%, 15%, 10%, or 5% areencompassed by the time period indicated.

If the stereochemistry of a structure or a portion thereof is notindicated, e.g., with bold or dashed lines, the structure or portionthereof is to be interpreted as encompassing all enantiomerically pure,enantiomerically enriched, diastereomerically pure, diastereomericallyenriched, and racemic mixtures of the compounds.

Unless otherwise indicated, the terms “enantiomerically enriched” and“enantiomerically pure,” as used interchangeably herein, refer tocompositions in which the percent by weight of one enantiomer is greaterthan the amount of that one enantiomer in a control mixture of theracemic composition (e.g., greater than 1:1 by weight). For example, anenantiomerically enriched preparation of the (S)-enantiomer, means apreparation of the compound having greater than 50% by weight of the(S)-enantiomer relative to the (R)-enantiomer, such as at least 75% byweight, and even such as at least 80% by weight. In some embodiments,the enrichment can be much greater than 80% by weight, providing a“substantially optically enriched,” “substantially enantiomericallyenriched,” “substantially enantiomerically pure” or a “substantiallynon-racemic” preparation, which refers to preparations of compositionswhich have at least 85% by weight of one enantiomer relative to otherenantiomer, such as at least 90% by weight, and such as at least 95% byweight. In some embodiments, the enantiomerically enriched compositionhas a higher potency with respect to therapeutic utility per unit massthan does the racemic mixture of that composition.

As used herein, and unless otherwise indicated, the term “hydrogenation”refers to a chemical process that adds hydrogen atom, or an isotopethereof (i.e., deuterium or tritium) to an unsaturated bond.

The disclosure can be understood more fully by reference to thefollowing detailed description and illustrative examples, which areintended to exemplify non-limiting embodiments.

Although most embodiments and examples provided herein are directed tothe (S)-enantiomer of an aminosulfone or an isoindoline compound, it isto be understood that the corresponding (R)-enantiomer can be preparedby the processes provided herein when the stereochemistry of chiralreactant, reagent, solvent, catalyst, ligand or the like is reversed. Itis also to be understood that the corresponding racemic compounds can beprepared by the processes provided herein when the correspondingnon-chiral reactant, reagent, solvent, catalyst, ligand or the like isused in place of the chiral reactant, reagent, solvent, catalyst, ligandor the like.

4.2 Processes

Provided herein are processes for the preparation of isoindolecompounds, or isotopologues thereof. In one embodiment, provided hereinare processes for the preparation of enantiomerically enriched orenantiomerically pure isoindole compounds, or isotopologues thereof.

In one embodiment, provided herein is a process for the preparation ofan enantiomerically enriched or enantiomerically pure compound ofFormula (I):

or a salt, solvate including a hydrate, stereoisomer, isotopologue, orpolymorph thereof, wherein:

-   -   R¹ and R² are each independently hydrogen, halogen, substituted        or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted        (C₁-C₆)alkoxy, (C₃-C₁₈)cycloalkyl, (C₃-C₆)cycloalkoxy, cyano,        —CF₃, (C₃-C₁₈)cycloalkyl-(C₁-C₆)alkoxy, or an isotopologue        thereof;    -   R³ is (C₁-C₆)alkyl, or an isotopologue thereof;    -   R is (C₁-C₃)alkyl, (C₃-C₆)cycloalkyl, or an isotopologue        thereof;    -   Z is C═O, methylene, or an isotopologue thereof; and    -   Y¹, Y², and Y³ are independently hydrogen or deuterium;        comprising the step of    -   (a) reducing an enamine of Formula (II):

or a salt or isotopologue thereof, via hydrogenation with hydrogen gasor deuterium gas, in a solvent, and in the presence of (1) a metalcatalyst and a chiral ligand or (2) a chiral metal catalyst/ligandcomplex to form an enantiomerically enriched or enantiomerically pureaminosulfone of Formula (III):

or a salt or isotopologue thereof.

In one embodiment, R¹ and R² are substituted or unsubstituted(C₁-C₆)alkoxy, or an isotopologue thereof. In one embodiment, R¹ is OMe,or an isotopologue thereof; R² is OEt, or an isotopologue thereof; andR³ is Me, or an isotopologue thereof. In one embodiment, R¹ is OMeenriched with 0, 1, 2, or 3 deuterium; R² is OEt enriched with 0, 1, 2,3, 4, or 5 deuterium; and R³ is Me enriched with 0, 1, 2, or 3deuterium. In one embodiment, R¹ is OCH₃. In another embodiment, R¹ isOCD₃. In one embodiment, R² is OCH₂CH₃. In another embodiment, R² isOCD₂CD₃. In one embodiment, R¹ is OCD₃ and R² is OCH₂CH₃. In anotherembodiment, R¹ is OCH₃ and R² is OCD₂CD₃. In yet another embodiment, R¹is OCD₃ and R² is OCD₂CD₃.

In one embodiment, Y¹ is hydrogen or deuterium, and Y² and Y³ are bothhydrogen or both deuterium. In one embodiment, Y¹, Y² and Y³ are allhydrogen. In another embodiment, Y¹ is hydrogen, and Y² and Y³ are bothdeuterium. In yet another embodiment, Y¹ is deuterium, and Y² and Y³ areboth hydrogen. In yet another embodiment, Y¹, Y² and Y³ are alldeuterium.

In one embodiment, Y¹ is hydrogen or deuterium, Y² is hydrogen, and Y³is deuterium. In another embodiment, Y¹ is hydrogen or deuterium, Y² isdeuterium, and Y³ is hydrogen.

In one embodiment of step (a), the hydrogenation occurs to an enamine ofFormula (II), or an isotopologue thereof, in free base form. In anotherembodiment of step (a), the hydrogenation occurs to an enamine ofFormula (II), or an isotopologue thereof, in a salt form. In oneembodiment, the hydrogenation occurs to an enamine of Formula (II), oran isotopologue thereof, in hydrochloride salt form.

In some embodiments, an enamine of Formula (II), or a salt orisotopologue thereof, may be synthesized based upon the routes describedin International Application Publication No. WO2012/097116, or othertechniques known in the art. In one embodiment, an enamine of Formula(II), or a salt or isotopologue thereof, is synthesized by reacting anitrile of Formula (IV):

or an isotopologue thereof, with LiCH₂SO₂R³, or an isotopologue thereof

In one embodiment, the enamine of Formula (II), or a salt orisotopologue thereof, is an enamine of Formula (II-a):

or a salt or isotopologue thereof. In one embodiment, an enamine ofFormula (II-a), or a salt or isotopologue thereof, is synthesized byreacting a nitrile of Formula (IV), or an isotopologue thereof, withCH₃SO₂CH₃ and n-BuLi.

In one embodiment, the enamine of Formula (II), or a salt orisotopologue thereof, is an enamine of Formula (II-b):

or a salt or isotopologue thereof. In one embodiment, an enamine ofFormula (II-b), or a salt or isotopologue thereof, is synthesized byreacting a nitrile of Formula (IV), or an isotopologue thereof, withCD₃SO₂CD₃ and n-BuLi.

It is to be understood that an enamine of Formula (II) also refers toits imine tautomer of Formula (II′). In one embodiment, thehydrogenation in step (a) occurs with hydrogen gas. In anotherembodiment, the hydrogenation in step (a) occurs with deuterium gas.

The hydrogenation in step (a) can occur in a solvent, or a mixture ofsolvents, that is suitable to promote catalytic asymmetrichydrogenation. For example, the hydrogenation in step (a) can occur in asolvent such as, but not limited to, ethyl acetate, diethyl ether,tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, chloroform,N-methyl pyrrolidinone, N,N-dimethyl-formamide, dimethyl sulfoxide,formic acid, acetic acid, methanol, ethanol, isopropanol,2,2,2-trifluoroethanol, and mixtures and isotopologues thereof.

In one embodiment, the hydrogenation in step (a) occurs in a solventcontaining exchangeable deuterium for proton-deuterium exchange. In oneembodiment, a —CH— group attached to the sulfone in an enamine ofFormula (II) or a —CH₂— or —CHD- group attached to the sulfone group inan imine of Formula (II′) can undergo proton-deuterium exchange in asolvent containing exchangeable deuterium for proton-deuterium exchangeto form a —CD₂- group. In one embodiment, the solvent containingexchangeable deuterium for proton-deuterium exchange is2,2,2-trifluoroethanol-d¹ (i.e., CF₃CH₂OD or d¹-TFE). In anotherembodiment, the solvent containing exchangeable deuterium forproton-deuterium exchange is 2,2,2-trifluoroethanol-d³ (i.e., CF₃CD₂ODor d³-TFE).

In one embodiment, the hydrogenation in step (a) occurs in a solventcontaining exchangeable proton for proton-deuterium exchange. In oneembodiment, a —CD- group attached to the sulfone in an enamine ofFormula (II) or a —CD₂- or —CHD- group attached to the sulfone group inan imine of Formula (II′) can undergo proton-deuterium exchange in asolvent containing exchangeable proton for proton-deuterium exchange toform a —CH₂— group. In one embodiment, the solvent containingexchangeable proton for proton-deuterium exchange is2,2,2-trifluoroethanol (i.e., CF₃CH₂OH or TFE).

In one embodiment of step (a), the hydrogenation is conducted withhydrogen gas in a solvent containing exchangeable proton forproton-deuterium exchange, and the enantiomerically enriched orenantiomerically pure aminosulfone formed is of Formula (III-a):

In one embodiment of step (a), the hydrogenation is conducted withdeuterium gas in a solvent containing exchangeable proton forproton-deuterium exchange, and the enantiomerically enriched orenantiomerically pure aminosulfone formed is of Formula (III-b):

In one embodiment of step (a), the hydrogenation is conducted withhydrogen gas in a solvent containing exchangeable deuterium forproton-deuterium exchange, and the enantiomerically enriched orenantiomerically pure aminosulfone formed is of Formula (III-c):

In one embodiment of step (a), the hydrogenation is conducted withdeuterium gas in a solvent containing exchangeable deuterium forproton-deuterium exchange, and the enantiomerically enriched orenantiomerically pure aminosulfone formed is of Formula (III-d):

In one embodiment, provided herein is a process for the preparation ofan enantiomerically enriched or enantiomerically pure compound ofFormula (I):

or a salt, solvate including a hydrate, stereoisomer, isotopologue, orpolymorph thereof, wherein:

-   -   R¹ and R² are each independently hydrogen, halogen, substituted        or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted        (C₁-C₆)alkoxy, (C₃-C₁₈)cycloalkyl, (C₃-C₆)cycloalkoxy, cyano,        —CF₃, (C₃-C₁₈)cycloalkyl-(C₁-C₆)alkoxy, or an isotopologue        thereof;    -   R³ is (C₁-C₆)alkyl, or an isotopologue thereof;    -   R is (C₁-C₃)alkyl, (C₃-C₆)cycloalkyl, or an isotopologue        thereof;    -   Z is C═O, methylene, or an isotopologue thereof; and    -   Y¹, Y², and Y³ are independently hydrogen or deuterium;    -   wherein not all of Y¹, Y², and Y³ are hydrogen;        comprising the step of    -   (a) reducing an enamine of Formula (II):

or a salt or isotopologue thereof, via hydrogenation with hydrogen gasor deuterium gas, in a solvent, and in the presence of (1) a metalcatalyst and a chiral ligand or (2) a chiral metal catalyst/ligandcomplex to form an enantiomerically enriched or enantiomerically pureaminosulfone of Formula (III):

or a salt or isotopologue thereof; wherein deuterium gas or a solventcontaining exchangeable deuterium for proton-deuterium exchange or bothis used.

In one embodiment, provided herein is a process for the preparation ofan enantiomerically enriched or enantiomerically pure compound ofFormula (I):

or a salt, solvate including a hydrate, stereoisomer, isotopologue, orpolymorph thereof, wherein:

-   -   R¹ and R² are each independently hydrogen, halogen, substituted        or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted        (C₁-C₆)alkoxy, (C₃-C₁₈)cycloalkyl, (C₃-C₆)cycloalkoxy, cyano,        —CF₃, (C₃-C₁₈)cycloalkyl-(C₁-C₆)alkoxy, or an isotopologue        thereof;    -   R³ is (C₁-C₆)alkyl, or an isotopologue thereof;    -   R is (C₁-C₃)alkyl, (C₃-C₆)cycloalkyl, or an isotopologue        thereof;    -   Z is C═O, methylene, or an isotopologue thereof;    -   Y¹ is hydrogen or deuterium; and    -   Y² and Y³ are both deuterium;        comprising the step of    -   (a) reducing an enamine of Formula (II):

or a salt or isotopologue thereof, via hydrogenation with hydrogen gasor deuterium gas, in a solvent containing exchangeable deuterium forproton-deuterium exchange, and in the presence of (1) a metal catalystand a chiral ligand or (2) a chiral metal catalyst/ligand complex toform an enantiomerically enriched or enantiomerically pure aminosulfoneof Formula (III):

or a salt or isotopologue thereof.

The metal catalyst can be any metal catalyst that is capable ofpromoting hydrogenation. In one embodiment, the metal catalyst containsa metal such as, but not limited to, copper, nickel, palladium,platinum, rhodium, iridium, and ruthenium. In one embodiment, the metalcatalyst contains rhodium. In another embodiment, the metal catalystcontains ruthenium. In yet another embodiment, the metal catalystcontains iridium. In one embodiment, the metal catalyst is Rh(cod)₂OTf.In another embodiment, the metal catalyst is Rh(cod)₂BF₄. In yet anotherembodiment, the metal catalyst is [Ir(cod)Cl]₂.

The chiral ligand or chiral metal catalyst/ligand complex can be anychiral ligand or chiral metal catalyst/ligand complex that is capable ofpromoting asymmetric hydrogenation. In one embodiment, the chiral ligandor chiral metal catalyst/ligand complex is, but not limited to, (S,R)-t-Bu Josiphos, Josiphos SL-J011-2, (S,S)-Me-Duphos, (S,S)-Chiraphos,(R)-Phanephos, (R)—Ru(OAc)₂(DM-segphos), [(R,R)-Me-BPE]Rh(cod)BF₄,(R)—C₃-TunePhos, (R)-[Rh(cod)TCFP]BF₄, or a stereoisomer thereof. In oneembodiment, the chiral ligand is (S, R)-t-Bu Josiphos or JosiphosSL-J011-2. In one embodiment, the chiral ligand is (S, R)-t-Bu Josiphos.In another embodiment, the chiral ligand is Josiphos SL-J011-2. Inanother embodiment, the chiral ligand is (R, S)-t-Bu Josiphos.

The hydrogenation can occur with a load of catalyst no less than about0.025 mol %. In general, the higher the load of catalyst, the higher theconversion and the shorter the reaction time. However, when the load ofcatalyst is sufficiently high, the yield of desired product may decreasedue to competing side reactions. In one embodiment, the load of catalystis between about 0.025 mol % and about 20 mol %. In one embodiment, theload of catalyst is between about 0.025 mol % and about 10 mol %. In oneembodiment, the load of catalyst is between about 0.05 mol % and about 5mol %. In one embodiment, the load of catalyst is between about 0.05 mol% and about 2.5 mol %. In one embodiment, the load of catalyst isbetween about 0.05 mol % and about 1 mol %. In one embodiment, the loadof catalyst is between about 0.05 mol % and about 0.25 mol %. In oneembodiment, the load of catalyst is about 5 mol %. In anotherembodiment, the load of catalyst is about 1 mol %. In yet anotherembodiment, the load of catalyst is about 0.25 mol %.

The molar ratio of the chiral ligand to the metal catalyst can be anyratio that is capable of promoting hydrogenation. In one embodiment, themolar ratio of the chiral ligand to the metal catalyst is from about 3:1to about 1:3. In one embodiment, the molar ratio of the chiral ligand tothe metal catalyst is from about 3:1 to about 1:1. In one embodiment,the molar ratio of the chiral ligand to the metal catalyst is about 2:1.In another embodiment, the molar ratio of the chiral ligand to the metalcatalyst is about 1:1.

The hydrogenation can occur under a hydrogen (or deuterium) pressurebetween about 1 psia and about 550 psia. In general, the higher thehydrogen pressure, the shorter is the reaction time. In one embodiment,the hydrogen pressure is between about 15 psig and about 250 psig. Inone embodiment, the hydrogen pressure is between about 15 psig and about90 psig. In another embodiment, the hydrogen pressure is between about90 psig and about 250 psig. In one embodiment, the hydrogen pressure isabout 15 psig. In another embodiment, the hydrogen pressure is about 90psig. In yet another embodiment, the hydrogen pressure is about 250psig.

The reaction temperature for the hydrogenation can be between about 10°C. and about 90° C. In one embodiment, the reaction temperature isbetween about 40° C. and about 60° C. In one embodiment, the reactiontemperature is about 50° C.

The reaction time for the hydrogenation can vary from about 1 to about72 hours, depending on the reaction temperature and the hydrogenpressure. In general, the higher the reaction temperature and the higherthe hydrogen pressure, the shorter is the reaction time.

In one embodiment, R is (C₁-C₃)alkyl, or an isotopologue thereof. In oneembodiment, R is methyl, or an isotopologue thereof. In one embodiment,R is methyl enriched with 0, 1, 2, or 3 deuterium.

4.2.1 Preparation of Isoindolin-1,3-dione Compounds

In one embodiment, provided herein is a process for the preparation ofan enantiomerically enriched or enantiomerically pure compound ofFormula (I-a):

or a salt, solvate including a hydrate, stereoisomer, isotopologue, orpolymorph thereof, wherein:

-   -   R¹ and R² are each independently hydrogen, halogen, substituted        or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted        (C₁-C₆)alkoxy, (C₃-C₁₈)cycloalkyl, (C₃-C₆)cycloalkoxy, cyano,        —CF₃, (C₃-C₁₈)cycloalkyl-(C₁-C₆)alkoxy, or an isotopologue        thereof;    -   R³ is (C₁-C₆)alkyl, or an isotopologue thereof;    -   R is (C₁-C₃)alkyl, (C₃-C₆)cycloalkyl, or an isotopologue        thereof; and    -   Y¹, Y², and Y³ are independently hydrogen or deuterium;        comprising the steps of    -   (a) reducing an enamine of Formula (II):

or a salt or isotopologue thereof, via hydrogenation with hydrogen gasor deuterium gas, in a solvent, and in the presence of (1) a metalcatalyst and a chiral ligand or (2) a chiral metal catalyst/ligandcomplex to form an enantiomerically enriched or enantiomerically pureaminosulfone of Formula (III):

or a salt or isotopologue thereof; and

-   -   (b) reacting the enantiomerically enriched or enantiomerically        pure aminosulfone of Formula (III), or a salt or isotopologue        thereof, with a compound of Formula (V):

or a salt or isotopologue thereof, to form the enantiomerically enrichedor enantiomerically pure compound of Formula (I-a), or a salt orisotopologue thereof.

In one embodiment, provided herein is a process for the preparation ofan enantiomerically enriched or enantiomerically pure compound ofFormula (I-a):

or a salt, solvate including a hydrate, stereoisomer, isotopologue, orpolymorph thereof, wherein:

-   -   R¹ and R² are each independently hydrogen, halogen, substituted        or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted        (C₁-C₆)alkoxy, (C₃-C₁₈)cycloalkyl, (C₃-C₆)cycloalkoxy, cyano,        —CF₃, (C₃-C₁₈)cycloalkyl-(C₁-C₆)alkoxy, or an isotopologue        thereof;    -   R³ is (C₁-C₆)alkyl, or an isotopologue thereof;    -   R is (C₁-C₃)alkyl, (C₃-C₆)cycloalkyl, or an isotopologue        thereof; and    -   Y¹, Y², and Y³ are independently hydrogen or deuterium;    -   wherein not all of Y¹, Y², and Y³ are hydrogen;        comprising the steps of    -   (a) reducing an enamine of Formula (II):

or a salt or isotopologue thereof, via hydrogenation with hydrogen gasor deuterium gas, in a solvent, and in the presence of (1) a metalcatalyst and a chiral ligand or (2) a chiral metal catalyst/ligandcomplex to form an enantiomerically enriched or enantiomerically pureaminosulfone of Formula (III):

or a salt or isotopologue thereof; wherein deuterium gas or a solventcontaining exchangeable deuterium for proton-deuterium exchange or bothis used; and

-   -   (b) reacting the enantiomerically enriched or enantiomerically        pure aminosulfone of Formula (III), or a salt or isotopologue        thereof, with a compound of Formula (V):

or a salt or isotopologue thereof, to form the enantiomerically enrichedor enantiomerically pure compound of Formula (I-a), or a salt orisotopologue thereof

In one embodiment, provided herein is a process for the preparation ofan enantiomerically enriched or enantiomerically pure compound ofFormula (I-a):

or a salt, solvate including a hydrate, stereoisomer, isotopologue, orpolymorph thereof, wherein:

-   -   R¹ and R² are each independently hydrogen, halogen, substituted        or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted        (C₁-C₆)alkoxy, (C₃-C₁₈)cycloalkyl, (C₃-C₆)cycloalkoxy, cyano,        —CF₃, (C₃-C₁₈)cycloalkyl-(C₁-C₆)alkoxy, or an isotopologue        thereof;    -   R³ is (C₁-C₆)alkyl, or an isotopologue thereof;    -   R is (C₁-C₃)alkyl, (C₃-C₆)cycloalkyl, or an isotopologue        thereof;    -   Y¹ is hydrogen or deuterium; and    -   Y² and Y³ are both deuterium;        comprising the steps of    -   (a) reducing an enamine of Formula (II):

or a salt or isotopologue thereof, via hydrogenation with hydrogen gasor deuterium gas, in a solvent containing exchangeable deuterium forproton-deuterium exchange, and in the presence of (1) a metal catalystand a chiral ligand or (2) a chiral metal catalyst/ligand complex toform an enantiomerically enriched or enantiomerically pure aminosulfoneof Formula (III):

or a salt or isotopologue thereof; and

-   -   (b) reacting the enantiomerically enriched or enantiomerically        pure aminosulfone of Formula (III), or a salt or isotopologue        thereof, with a compound of Formula (V):

or a salt or isotopologue thereof, to form the enantiomerically enrichedor enantiomerically pure compound of Formula (I-a), or a salt orisotopologue thereof

In one embodiment, R is (C₁-C₃)alkyl, or an isotopologue thereof. In oneembodiment, R is methyl, or an isotopologue thereof. In one embodiment,R is methyl enriched with 0, 1, 2, or 3 deuterium. In one embodiment, Ris CD₃.

Step (a) is as described herein and elsewhere above.

In some embodiments of step (b), the reaction of the enantiomericallyenriched or enantiomerically pure aminosulfone of Formula (III), or asalt or isotopologue thereof, with a compound of Formula (V), or a saltor isotopologue thereof, may be conducted based upon the routesdescribed in International Application Publication No. WO2012/097116 andU.S. Pat. No. 6,962,940, the entireties of which are incorporated hereinby reference. In one embodiment of step (b), the reaction occurs in asolvent (e.g., acetic acid) via heating (e.g., refluxing).

In one embodiment, provided herein is a process for the preparation ofan enantiomerically enriched or enantiomerically pure compound ofFormula (I-a-1):

or a salt, solvate including a hydrate, stereoisomer, isotopologue, orpolymorph thereof, wherein:

-   -   R¹ is OMe enriched with 0, 1, 2, or 3 deuterium;    -   R² is OEt enriched with 0, 1, 2, 3, 4, or 5 deuterium; and    -   R is methyl enriched with 0, 1, 2, or 3 deuterium;        comprising the steps of    -   (a) reducing an enamine of Formula (II-a):

or a salt or isotopologue thereof, via hydrogenation with hydrogen gas,in a solvent not containing exchangeable deuterium (including a solventcontaining exchangeable proton for proton-deuterium exchange, such asTFE), and in the presence of (1) a metal catalyst and a chiral ligand or(2) a chiral metal catalyst/ligand complex to form an enantiomericallyenriched or enantiomerically pure aminosulfone of Formula (III-1):

or a salt or isotopologue thereof; and

-   -   (b) reacting the enantiomerically enriched or enantiomerically        pure aminosulfone of Formula (III-1), or a salt or isotopologue        thereof, with a compound of Formula (V):

or a salt or isotopologue thereof, to form the enantiomerically enrichedor enantiomerically pure compound of Formula (I-a-1), or a salt orisotopologue thereof

In one embodiment, provided herein is a process for the preparation ofan enantiomerically enriched or enantiomerically pure compound ofFormula (I-a-2):

or a salt, solvate including a hydrate, stereoisomer, isotopologue, orpolymorph thereof, wherein:

-   -   R¹ is OMe enriched with 0, 1, 2, or 3 deuterium;    -   R² is OEt enriched with 0, 1, 2, 3, 4, or 5 deuterium; and    -   R is methyl enriched with 0, 1, 2, or 3 deuterium;        comprising the steps of    -   (a) reducing an enamine of Formula (II-a):

or a salt or isotopologue thereof, via hydrogenation with deuterium gas,in a solvent containing exchangeable proton for proton-deuteriumexchange, and in the presence of (1) a metal catalyst and a chiralligand or (2) a chiral metal catalyst/ligand complex to form anenantiomerically enriched or enantiomerically pure aminosulfone ofFormula (III-2):

or a salt or isotopologue thereof; and

-   -   (b) reacting the enantiomerically enriched or enantiomerically        pure aminosulfone of Formula (III-2), or a salt or isotopologue        thereof, with a compound of Formula (V):

or a salt or isotopologue thereof, to form the enantiomerically enrichedor enantiomerically pure compound of Formula (I-a-2), or a salt orisotopologue thereof

In one embodiment, provided herein is a process for the preparation ofan enantiomerically enriched or enantiomerically pure compound ofFormula (I-a-3):

or a salt, solvate including a hydrate, stereoisomer, isotopologue, orpolymorph thereof, wherein:

-   -   R¹ is OMe enriched with 0, 1, 2, or 3 deuterium;    -   R² is OEt enriched with 0, 1, 2, 3, 4, or 5 deuterium; and    -   R is methyl enriched with 0, 1, 2, or 3 deuterium;        comprising the steps of    -   (a) reducing an enamine of Formula (II-a):

or a salt or isotopologue thereof, via hydrogenation with hydrogen gas,in a solvent containing exchangeable deuterium for proton-deuteriumexchange, and in the presence of (1) a metal catalyst and a chiralligand or (2) a chiral metal catalyst/ligand complex to form anenantiomerically enriched or enantiomerically pure aminosulfone ofFormula (III-3):

or a salt or isotopologue thereof; and

-   -   (b) reacting the enantiomerically enriched or enantiomerically        pure aminosulfone of Formula (III-3), or a salt or isotopologue        thereof, with a compound of Formula (V):

or a salt or isotopologue thereof, to form the enantiomerically enrichedor enantiomerically pure compound of Formula (I-a-3), or a salt orisotopologue thereof

In one embodiment, provided herein is a process for the preparation ofan enantiomerically enriched or enantiomerically pure compound ofFormula (I-a-4):

or a salt, solvate including a hydrate, stereoisomer, isotopologue, orpolymorph thereof, wherein:

-   -   R¹ is OMe enriched with 0, 1, 2, or 3 deuterium;    -   R² is OEt enriched with 0, 1, 2, 3, 4, or 5 deuterium; and    -   R is methyl enriched with 0, 1, 2, or 3 deuterium;        comprising the steps of    -   (a) reducing an enamine of Formula (II-a):

or a salt or isotopologue thereof, via hydrogenation with deuterium gas,in a solvent containing exchangeable deuterium for proton-deuteriumexchange, and in the presence of (1) a metal catalyst and a chiralligand or (2) a chiral metal catalyst/ligand complex to form anenantiomerically enriched or enantiomerically pure aminosulfone ofFormula (III-4):

or a salt or isotopologue thereof; and

-   -   (b) reacting the enantiomerically enriched or enantiomerically        pure aminosulfone of Formula (III-4), or a salt or isotopologue        thereof, with a compound of Formula (V):

or a salt or isotopologue thereof, to form the enantiomerically enrichedor enantiomerically pure compound of Formula (I-a-4), or a salt orisotopologue thereof

In one embodiment, provided herein is a process for the preparation ofan enantiomerically enriched or enantiomerically pure compound ofFormula (I-a-5):

or a salt, solvate including a hydrate, stereoisomer, isotopologue, orpolymorph thereof, wherein:

-   -   R¹ is OMe enriched with 0, 1, 2, or 3 deuterium;    -   R² is OEt enriched with 0, 1, 2, 3, 4, or 5 deuterium; and    -   R is methyl enriched with 0, 1, 2, or 3 deuterium;        comprising the steps of    -   (a) reducing an enamine of Formula (II-b):

or a salt or isotopologue thereof, via hydrogenation with hydrogen gas,in a solvent containing exchangeable proton for proton-deuteriumexchange, and in the presence of (1) a metal catalyst and a chiralligand or (2) a chiral metal catalyst/ligand complex to form anenantiomerically enriched or enantiomerically pure aminosulfone ofFormula (III-5):

or a salt or isotopologue thereof; and

-   -   (b) reacting the enantiomerically enriched or enantiomerically        pure aminosulfone of Formula (III-5), or a salt or isotopologue        thereof, with a compound of Formula (V):

or a salt or isotopologue thereof, to form the enantiomerically enrichedor enantiomerically pure compound of Formula (I-a-5), or a salt orisotopologue thereof

In one embodiment, provided herein is a process for the preparation ofan enantiomerically enriched or enantiomerically pure compound ofFormula (I-a-6):

or a salt, solvate including a hydrate, stereoisomer, isotopologue, orpolymorph thereof, wherein:

-   -   R¹ is OMe enriched with 0, 1, 2, or 3 deuterium;    -   R² is OEt enriched with 0, 1, 2, 3, 4, or 5 deuterium; and    -   R is methyl enriched with 0, 1, 2, or 3 deuterium;        comprising the steps of    -   (a) reducing an enamine of Formula (II-b):

or a salt or isotopologue thereof, via hydrogenation with deuterium gas,in a solvent containing exchangeable proton for proton-deuteriumexchange, and in the presence of (1) a metal catalyst and a chiralligand or (2) a chiral metal catalyst/ligand complex to form anenantiomerically enriched or enantiomerically pure aminosulfone ofFormula (III-6):

or a salt or isotopologue thereof; and

-   -   (b) reacting the enantiomerically enriched or enantiomerically        pure aminosulfone of Formula (III-6), or a salt or isotopologue        thereof, with a compound of Formula (V):

or a salt or isotopologue thereof, to form the enantiomerically enrichedor enantiomerically pure compound of Formula (I-a-6), or a salt orisotopologue thereof

In one embodiment, provided herein is a process for the preparation ofan enantiomerically enriched or enantiomerically pure compound ofFormula (I-a-7):

or a salt, solvate including a hydrate, stereoisomer, isotopologue, orpolymorph thereof, wherein:

-   -   R¹ is OMe enriched with 0, 1, 2, or 3 deuterium;    -   R² is OEt enriched with 0, 1, 2, 3, 4, or 5 deuterium; and    -   R is methyl enriched with 0, 1, 2, or 3 deuterium;        comprising the steps of    -   (a) reducing an enamine of Formula (II-b):

or a salt or isotopologue thereof, via hydrogenation with hydrogen gas,in a solvent containing exchangeable deuterium for proton-deuteriumexchange, and in the presence of (1) a metal catalyst and a chiralligand or (2) a chiral metal catalyst/ligand complex to form anenantiomerically enriched or enantiomerically pure aminosulfone ofFormula (III-7):

or a salt or isotopologue thereof; and

-   -   (b) reacting the enantiomerically enriched or enantiomerically        pure aminosulfone of Formula (III-7), or a salt or isotopologue        thereof, with a compound of Formula (V):

or a salt or isotopologue thereof, to form the enantiomerically enrichedor enantiomerically pure compound of Formula (I-a-7), or a salt orisotopologue thereof

In one embodiment, provided herein is a process for the preparation ofan enantiomerically enriched or enantiomerically pure compound ofFormula (I-a-8):

or a salt, solvate including a hydrate, stereoisomer, isotopologue, orpolymorph thereof, wherein:

-   -   R¹ is OMe enriched with 0, 1, 2, or 3 deuterium;    -   R² is OEt enriched with 0, 1, 2, 3, 4, or 5 deuterium; and    -   R is methyl enriched with 0, 1, 2, or 3 deuterium;        comprising the steps of    -   (a) reducing an enamine of Formula (II-b):

or a salt or isotopologue thereof, via hydrogenation with deuterium gas,in a solvent not containing exchangeable proton (including a solventcontaining exchangeable deuterium for proton-deuterium exchange, such asd₁-TFE), and in the presence of (1) a metal catalyst and a chiral ligandor (2) a chiral metal catalyst/ligand complex to form anenantiomerically enriched or enantiomerically pure aminosulfone ofFormula (III-8):

or a salt or isotopologue thereof; and

-   -   (b) reacting the enantiomerically enriched or enantiomerically        pure aminosulfone of Formula (III-8), or a salt or isotopologue        thereof, with a compound of Formula (V):

or a salt or isotopologue thereof, to form the enantiomerically enrichedor enantiomerically pure compound of Formula (I-a-8), or a salt orisotopologue thereof

In one embodiment, an enantiomerically enriched or enantiomerically purecompound of Formula (I-a), or an isotopologue thereof, is a compound A:

or an isotopologue thereof.

4.2.2 Preparation of Isoindolin-1-One Compounds

In one embodiment, provided herein is a process for the preparation ofan enantiomerically enriched or enantiomerically pure compound ofFormula (I-b):

or a salt, solvate including a hydrate, stereoisomer, isotopologue, orpolymorph thereof, wherein:

-   -   R¹ and R² are each independently hydrogen, halogen, substituted        or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted        (C₁-C₆)alkoxy, (C₃-C₁₈)cycloalkyl, (C₃-C₆)cycloalkoxy, cyano,        —CF₃, (C₃-C₁₈)cycloalkyl-(C₁-C₆)alkoxy, or an isotopologue        thereof;    -   R³ is (C₁-C₆)alkyl, or an isotopologue thereof;    -   R is (C₁-C₃)alkyl, (C₃-C₆)cycloalkyl, or an isotopologue        thereof; and    -   Y¹, Y², and Y³ are independently hydrogen or deuterium;        comprising the steps of    -   (a) reducing an enamine of Formula (II):

or a salt or isotopologue thereof, via hydrogenation with hydrogen gasor deuterium gas, in a solvent, and in the presence of (1) a metalcatalyst and a chiral ligand or (2) a chiral metal catalyst/ligandcomplex to form an enantiomerically enriched or enantiomerically pureaminosulfone of Formula (III):

or a salt or isotopologue thereof;

-   -   (b) reacting the enantiomerically enriched or enantiomerically        pure aminosulfone of Formula (III), or a salt or isotopologue        thereof, with a compound of Formula (VI):

or a salt or isotopologue thereof, wherein R⁴ is (C₁-C₃)alkyl, and X ishalogen, to form an enantiomerically enriched or enantiomerically purecompound of Formula (VII):

or a salt or isotopologue thereof;

-   -   (c) reducing the enantiomerically enriched or enantiomerically        pure compound of Formula (VII), or a salt or isotopologue        thereof, to form an enantiomerically enriched or        enantiomerically pure compound of Formula (VIII):

or a salt or isotopologue thereof; and

-   -   (d) reacting the enantiomerically enriched or enantiomerically        pure compound of Formula (VIII), or a salt or isotopologue        thereof, with an acid chloride RCOCl, or an isotopologue        thereof, to form the enantiomerically enriched or        enantiomerically pure compound of Formula (I-b), or a salt or        isotopologue thereof.

In one embodiment, provided herein is a process for the preparation ofan enantiomerically enriched or enantiomerically pure compound ofFormula (I-b):

or a salt, solvate including a hydrate, stereoisomer, isotopologue, orpolymorph thereof, wherein:

-   -   R¹ and R² are each independently hydrogen, halogen, substituted        or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted        (C₁-C₆)alkoxy, (C₃-C₁₈)cycloalkyl, (C₃-C₆)cycloalkoxy, cyano,        —CF₃, (C₃-C₁₈)cycloalkyl-(C₁-C₆)alkoxy, or an isotopologue        thereof;    -   R³ is (C₁-C₆)alkyl, or an isotopologue thereof;    -   R is (C₁-C₃)alkyl, (C₃-C₆)cycloalkyl, or an isotopologue        thereof; and    -   Y¹, Y², and Y³ are independently hydrogen or deuterium;    -   wherein not all of Y¹, Y², and Y³ are hydrogen;        comprising the steps of    -   (a) reducing an enamine of Formula (II):

or a salt or isotopologue thereof, via hydrogenation with hydrogen gasor deuterium gas, in a solvent, and in the presence of (1) a metalcatalyst and a chiral ligand or (2) a chiral metal catalyst/ligandcomplex to form an enantiomerically enriched or enantiomerically pureaminosulfone of Formula (III):

or a salt or isotopologue thereof; wherein deuterium gas or a solventcontaining exchangeable deuterium for proton-deuterium exchange or bothis used;

-   -   (b) reacting the enantiomerically enriched or enantiomerically        pure aminosulfone of Formula (III), or a salt or isotopologue        thereof, with a compound of Formula (VI):

or a salt or isotopologue thereof, wherein R⁴ is (C₁-C₃)alkyl, and X ishalogen, to form an enantiomerically enriched or enantiomerically purecompound of Formula (VII):

or a salt or isotopologue thereof;

-   -   (c) reducing the enantiomerically enriched or enantiomerically        pure compound of Formula (VII), or a salt or isotopologue        thereof, to form an enantiomerically enriched or        enantiomerically pure compound of Formula (VIII):

or a salt or isotopologue thereof; and

-   -   (d) reacting the enantiomerically enriched or enantiomerically        pure compound of Formula (VIII), or a salt or isotopologue        thereof, with an acid chloride RCOCl, or an isotopologue        thereof, to form the enantiomerically enriched or        enantiomerically pure compound of Formula (I-b), or a salt or        isotopologue thereof.

In one embodiment, provided herein is a process for the preparation ofan enantiomerically enriched or enantiomerically pure compound ofFormula (I-b):

or a salt, solvate including a hydrate, stereoisomer, isotopologue, orpolymorph thereof, wherein:

-   -   R¹ and R² are each independently hydrogen, halogen, substituted        or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted        (C₁-C₆)alkoxy, (C₃-C₁₈)cycloalkyl, (C₃-C₆)cycloalkoxy, cyano,        —CF₃, (C₃-C₁₈)cycloalkyl-(C₁-C₆)alkoxy, or an isotopologue        thereof;    -   R³ is (C₁-C₆)alkyl, or an isotopologue thereof    -   R is (C₁-C₃)alkyl, (C₃-C₆)cycloalkyl, or an isotopologue thereof    -   Y¹ is hydrogen or deuterium; and    -   Y² and Y³ are both deuterium;        comprising the steps of    -   (a) reducing an enamine of Formula (II):

or a salt or isotopologue thereof, via hydrogenation with hydrogen gasor deuterium gas, in a solvent containing exchangeable deuterium forproton-deuterium exchange, and in the presence of (1) a metal catalystand a chiral ligand or (2) a chiral metal catalyst/ligand complex toform an enantiomerically enriched or enantiomerically pure aminosulfoneof Formula (III):

or a salt or isotopologue thereof;

-   -   (b) reacting the enantiomerically enriched or enantiomerically        pure aminosulfone of Formula (III), or a salt or isotopologue        thereof, with a compound of Formula (VI):

or a salt or isotopologue thereof, wherein R⁴ is (C₁-C₃)alkyl, and X ishalogen, to form an enantiomerically enriched or enantiomerically purecompound of Formula (VII):

or a salt or isotopologue thereof;

-   -   (c) reducing the enantiomerically enriched or enantiomerically        pure compound of Formula (VII), or a salt or isotopologue        thereof, to form an enantiomerically enriched or        enantiomerically pure compound of Formula (VIII):

or a salt or isotopologue thereof; and

-   -   (d) reacting the enantiomerically enriched or enantiomerically        pure compound of Formula (VIII), or a salt or isotopologue        thereof, with an acid chloride RCOCl, or an isotopologue        thereof, to form the enantiomerically enriched or        enantiomerically pure compound of Formula (I-b), or a salt or        isotopologue thereof.

In one embodiment, R is (C₃-C₆)cycloalkyl, or an isotopologue thereof.In one embodiment, R is cyclopropyl, or an isotopologue thereof. In oneembodiment, R is cyclopropyl enriched with 0, 1, 2, 3, 4, or 5deuterium. In one embodiment, R is cyclopropyl enriched with 5deuterium.

Step (a) is described as herein and elsewhere above.

In some embodiments of step (b), the reaction of the enantiomericallyenriched or enantiomerically pure aminosulfone of Formula (III), or asalt or isotopologue thereof, with a compound of Formula (VI), or a saltor isotopologue thereof, may be conducted based upon the routesdescribed in International Application Publication No. WO2012/097116 andU.S. Pat. Nos. 6,667,316, 6,020,358, and 7,034,052, the entireties ofwhich are incorporated herein by reference. In one embodiment of step(b), R⁴ is methyl or ethyl, and X is bromo. In one embodiment of step(b), the reaction occurs in a solvent (e.g., DMF) via heating (e.g.,about 100° C.) in the presence of a base (e.g., triethylamine).

In some embodiments of step (c), the reduction of the enantiomericallyenriched or enantiomerically pure compound of Formula (VII), or a saltor isotopologue thereof, may be conducted based upon the routesdescribed in International Application Publication No. WO2012/097116 andU.S. Pat. Nos. 6,667,316, 6,020,358, and 7,034,052. In one embodiment ofstep (c), the reduction occurs via hydrogenation in a solvent (e.g.,ethyl acetate) in the presence of a metal catalyst (e.g., Pd/C).

In some embodiments of step (d), the reaction of the enantiomericallyenriched or enantiomerically pure compound of Formula (VIII), or a saltor isotopologue thereof, with an acid chloride RCOCl, or an isotopologuethereof, may be conducted based upon the routes described inInternational Application Publication No. WO2012/097116 and U.S. Pat.Nos. 6,667,316, 6,020,358, and 7,034,052. In one embodiment of step (d),the reaction occurs in a solvent (e.g., DMF) in the presence of a base(e.g., triethylamine).

In one embodiment, provided herein is a process for the preparation ofan enantiomerically enriched or enantiomerically pure compound ofFormula (I-b-1):

or a salt, solvate including a hydrate, stereoisomer, isotopologue, orpolymorph thereof, wherein:

-   -   R¹ is OMe enriched with 0, 1, 2, or 3 deuterium;    -   R² is OEt enriched with 0, 1, 2, 3, 4, or 5 deuterium;    -   R⁵ and R⁶ are independently hydrogen or deuterium; and    -   R is cyclopropyl enriched with 0, 1, 2, 3, 4, or 5 deuterium;        comprising the steps of    -   (a) reducing an enamine of Formula (II-a):

or a salt or isotopologue thereof, via hydrogenation with hydrogen gas,in a solvent not containing exchangeable deuterium (including a solventcontaining exchangeable proton for proton-deuterium exchange, such asTFE), and in the presence of (1) a metal catalyst and a chiral ligand or(2) a chiral metal catalyst/ligand complex to form an enantiomericallyenriched or enantiomerically pure aminosulfone of Formula (III-1):

or a salt or isotopologue thereof;

-   -   (b) reacting the enantiomerically enriched or enantiomerically        pure aminosulfone of Formula (III-1), or a salt or isotopologue        thereof, with a compound of Formula (VI-a):

or a salt or isotopologue thereof, wherein R⁴ is (C₁-C₃)alkyl, and X ishalogen, to form an enantiomerically enriched or enantiomerically purecompound of Formula (VIII-1):

or a salt or isotopologue thereof;

-   -   (c) reducing the enantiomerically enriched or enantiomerically        pure compound of Formula (VIII-1), or a salt or isotopologue        thereof, to form an enantiomerically enriched or        enantiomerically pure compound of Formula (IX-1):

or a salt or isotopologue thereof; and

-   -   (d) reacting the enantiomerically enriched or enantiomerically        pure compound of Formula (IX-1), or a salt or isotopologue        thereof, with an acid chloride RCOCl, or an isotopologue        thereof, to form the enantiomerically enriched or        enantiomerically pure compound of Formula (I-b-1), or a salt or        isotopologue thereof.

In one embodiment, provided herein is a process for the preparation ofan enantiomerically enriched or enantiomerically pure compound ofFormula (I-b-2):

or a salt, solvate including a hydrate, stereoisomer, isotopologue, orpolymorph thereof, wherein:

-   -   R¹ is OMe enriched with 0, 1, 2, or 3 deuterium;    -   R² is OEt enriched with 0, 1, 2, 3, 4, or 5 deuterium;    -   R⁵ and R⁶ are independently hydrogen or deuterium; and    -   R is cyclopropyl enriched with 0, 1, 2, 3, 4, or 5 deuterium;        comprising the steps of    -   (a) reducing an enamine of Formula (II-a):

or a salt or isotopologue thereof, via hydrogenation with deuterium gas,in a solvent containing exchangeable proton for proton-deuteriumexchange, and in the presence of (1) a metal catalyst and a chiralligand or (2) a chiral metal catalyst/ligand complex to form anenantiomerically enriched or enantiomerically pure aminosulfone ofFormula (III-2):

or a salt or isotopologue thereof;

-   -   (b) reacting the enantiomerically enriched or enantiomerically        pure aminosulfone of Formula (III-2), or a salt or isotopologue        thereof, with a compound of Formula (VI-a):

or a salt or isotopologue thereof, wherein R⁴ is (C₁-C₃)alkyl, and X ishalogen, to form an enantiomerically enriched or enantiomerically purecompound of Formula (VIII-2):

or a salt or isotopologue thereof;

-   -   (c) reducing the enantiomerically enriched or enantiomerically        pure compound of Formula (VIII-2), or a salt or isotopologue        thereof, to form an enantiomerically enriched or        enantiomerically pure compound of Formula (IX-2):

or a salt or isotopologue thereof; and

-   -   (d) reacting the enantiomerically enriched or enantiomerically        pure compound of Formula (IX-2), or a salt or isotopologue        thereof, with an acid chloride RCOCl, or an isotopologue        thereof, to form the enantiomerically enriched or        enantiomerically pure compound of Formula (I-b-2), or a salt or        isotopologue thereof.

In one embodiment, provided herein is a process for the preparation ofan enantiomerically enriched or enantiomerically pure compound ofFormula (I-b-3):

or a salt, solvate including a hydrate, stereoisomer, isotopologue, orpolymorph thereof, wherein:

-   -   R¹ is OMe enriched with 0, 1, 2, or 3 deuterium;    -   R² is OEt enriched with 0, 1, 2, 3, 4, or 5 deuterium;    -   R⁵ and R⁶ are independently hydrogen or deuterium; and    -   R is cyclopropyl enriched with 0, 1, 2, 3, 4, or 5 deuterium;        comprising the steps of    -   (a) reducing an enamine of Formula (II-a):

or a salt or isotopologue thereof, via hydrogenation with hydrogen gas,in a solvent containing exchangeable deuterium for proton-deuteriumexchange, and in the presence of (1) a metal catalyst and a chiralligand or (2) a chiral metal catalyst/ligand complex to form anenantiomerically enriched or enantiomerically pure aminosulfone ofFormula (III-3):

or a salt or isotopologue thereof;

-   -   (b) reacting the enantiomerically enriched or enantiomerically        pure aminosulfone of Formula (III-3), or a salt or isotopologue        thereof, with a compound of Formula (VI-a):

or a salt or isotopologue thereof, wherein R⁴ is (C₁-C₃)alkyl, and X ishalogen, to form an enantiomerically enriched or enantiomerically purecompound of Formula (VIII-3):

or a salt or isotopologue thereof;

-   -   (c) reducing the enantiomerically enriched or enantiomerically        pure compound of Formula (VIII-3), or a salt or isotopologue        thereof, to form an enantiomerically enriched or        enantiomerically pure compound of Formula (IX-3):

or a salt or isotopologue thereof; and

-   -   (d) reacting the enantiomerically enriched or enantiomerically        pure compound of Formula (IX-3), or a salt or isotopologue        thereof, with an acid chloride RCOCl, or an isotopologue        thereof, to form the enantiomerically enriched or        enantiomerically pure compound of Formula (I-b-3), or a salt or        isotopologue thereof.

In one embodiment, provided herein is a process for the preparation ofan enantiomerically enriched or enantiomerically pure compound ofFormula (I-b-4):

or a salt, solvate including a hydrate, stereoisomer, isotopologue, orpolymorph thereof, wherein:

-   -   R¹ is OMe enriched with 0, 1, 2, or 3 deuterium;    -   R² is OEt enriched with 0, 1, 2, 3, 4, or 5 deuterium;    -   R⁵ and R⁶ are independently hydrogen or deuterium; and    -   R is cyclopropyl enriched with 0, 1, 2, 3, 4, or 5 deuterium;        comprising the steps of    -   (a) reducing an enamine of Formula (II-a):

or a salt or isotopologue thereof, via hydrogenation with deuterium gas,in a solvent containing exchangeable deuterium for proton-deuteriumexchange, and in the presence of (1) a metal catalyst and a chiralligand or (2) a chiral metal catalyst/ligand complex to form anenantiomerically enriched or enantiomerically pure aminosulfone ofFormula (III-4):

or a salt or isotopologue thereof;

-   -   (b) reacting the enantiomerically enriched or enantiomerically        pure aminosulfone of Formula (III-4), or a salt or isotopologue        thereof, with a compound of Formula (VI-a):

or a salt or isotopologue thereof, wherein R⁴ is (C₁-C₃)alkyl, and X ishalogen, to form an enantiomerically enriched or enantiomerically purecompound of Formula (VIII-4):

or a salt or isotopologue thereof;

-   -   (c) reducing the enantiomerically enriched or enantiomerically        pure compound of Formula (VIII-4), or a salt or isotopologue        thereof, to form an enantiomerically enriched or        enantiomerically pure compound of Formula (IX-4):

or a salt or isotopologue thereof; and

-   -   (d) reacting the enantiomerically enriched or enantiomerically        pure compound of Formula (IX-4), or a salt or isotopologue        thereof, with an acid chloride RCOCl, or an isotopologue        thereof, to form the enantiomerically enriched or        enantiomerically pure compound of Formula (I-b-4), or a salt or        isotopologue thereof.

In one embodiment, provided herein is a process for the preparation ofan enantiomerically enriched or enantiomerically pure compound ofFormula (I-b-5):

or a salt, solvate including a hydrate, stereoisomer, isotopologue, orpolymorph thereof, wherein:

-   -   R¹ is OMe enriched with 0, 1, 2, or 3 deuterium;    -   R² is OEt enriched with 0, 1, 2, 3, 4, or 5 deuterium;    -   R⁵ and R⁶ are independently hydrogen or deuterium; and    -   R is cyclopropyl enriched with 0, 1, 2, 3, 4, or 5 deuterium;        comprising the steps of    -   (a) reducing an enamine of Formula (II-b):

or a salt or isotopologue thereof, via hydrogenation with hydrogen gas,in a solvent containing exchangeable proton for proton-deuteriumexchange, and in the presence of (1) a metal catalyst and a chiralligand or (2) a chiral metal catalyst/ligand complex to form anenantiomerically enriched or enantiomerically pure aminosulfone ofFormula (III-5):

or a salt or isotopologue thereof;

-   -   (b) reacting the enantiomerically enriched or enantiomerically        pure aminosulfone of Formula (III-5), or a salt or isotopologue        thereof, with a compound of Formula (VI-a):

or a salt or isotopologue thereof, wherein R⁴ is (C₁-C₃)alkyl, and X ishalogen, to form an enantiomerically enriched or enantiomerically purecompound of Formula (VIII-5):

or a salt or isotopologue thereof;

-   -   (c) reducing the enantiomerically enriched or enantiomerically        pure compound of Formula (VIII-5), or a salt or isotopologue        thereof, to form an enantiomerically enriched or        enantiomerically pure compound of Formula (IX-5):

or a salt or isotopologue thereof; and

-   -   (d) reacting the enantiomerically enriched or enantiomerically        pure compound of Formula (IX-5), or a salt or isotopologue        thereof, with an acid chloride RCOCl, or an isotopologue        thereof, to form the enantiomerically enriched or        enantiomerically pure compound of Formula (I-b-5), or a salt or        isotopologue thereof.

In one embodiment, provided herein is a process for the preparation ofan enantiomerically enriched or enantiomerically pure compound ofFormula (I-b-6):

or a salt, solvate including a hydrate, stereoisomer, isotopologue, orpolymorph thereof, wherein:

-   -   R¹ is OMe enriched with 0, 1, 2, or 3 deuterium;    -   R² is OEt enriched with 0, 1, 2, 3, 4, or 5 deuterium;    -   R⁵ and R⁶ are independently hydrogen or deuterium; and    -   R is cyclopropyl enriched with 0, 1, 2, 3, 4, or 5 deuterium;        comprising the steps of    -   (a) reducing an enamine of Formula (II-b):

or a salt or isotopologue thereof, via hydrogenation with deuterium gas,in a solvent containing exchangeable proton for proton-deuteriumexchange, and in the presence of (1) a metal catalyst and a chiralligand or (2) a chiral metal catalyst/ligand complex to form anenantiomerically enriched or enantiomerically pure aminosulfone ofFormula (III-6):

or a salt or isotopologue thereof;

-   -   (b) reacting the enantiomerically enriched or enantiomerically        pure aminosulfone of Formula (III-6), or a salt or isotopologue        thereof, with a compound of Formula (VI-a):

or a salt or isotopologue thereof, wherein R⁴ is (C₁-C₃)alkyl, and X ishalogen, to form an enantiomerically enriched or enantiomerically purecompound of Formula (VIII-6):

or a salt or isotopologue thereof;

-   -   (c) reducing the enantiomerically enriched or enantiomerically        pure compound of Formula (VIII-6), or a salt or isotopologue        thereof, to form an enantiomerically enriched or        enantiomerically pure compound of Formula (IX-6):

or a salt or isotopologue thereof; and

-   -   (d) reacting the enantiomerically enriched or enantiomerically        pure compound of Formula (IX-6), or a salt or isotopologue        thereof, with an acid chloride RCOCl, or an isotopologue        thereof, to form the enantiomerically enriched or        enantiomerically pure compound of Formula (I-b-6), or a salt or        isotopologue thereof.

In one embodiment, provided herein is a process for the preparation ofan enantiomerically enriched or enantiomerically pure compound ofFormula (I-b-7):

or a salt, solvate including a hydrate, stereoisomer, isotopologue, orpolymorph thereof, wherein:

-   -   R¹ is OMe enriched with 0, 1, 2, or 3 deuterium;    -   R² is OEt enriched with 0, 1, 2, 3, 4, or 5 deuterium;    -   R⁵ and R⁶ are independently hydrogen or deuterium; and    -   R is cyclopropyl enriched with 0, 1, 2, 3, 4, or 5 deuterium;        comprising the steps of    -   (a) reducing an enamine of Formula (II-b):

or a salt or isotopologue thereof, via hydrogenation with hydrogen gas,in a solvent containing exchangeable deuterium for proton-deuteriumexchange, and in the presence of (1) a metal catalyst and a chiralligand or (2) a chiral metal catalyst/ligand complex to form anenantiomerically enriched or enantiomerically pure aminosulfone ofFormula (III-7):

or a salt or isotopologue thereof;

-   -   (b) reacting the enantiomerically enriched or enantiomerically        pure aminosulfone of Formula (III-7), or a salt or isotopologue        thereof, with a compound of Formula (VI-a):

or a salt or isotopologue thereof, wherein R⁴ is (C₁-C₃)alkyl, and X ishalogen, to form an enantiomerically enriched or enantiomerically purecompound of Formula (VIII-7):

or a salt or isotopologue thereof;

-   -   (c) reducing the enantiomerically enriched or enantiomerically        pure compound of Formula (VIII-7), or a salt or isotopologue        thereof, to form an enantiomerically enriched or        enantiomerically pure compound of Formula (IX-7):

or a salt or isotopologue thereof; and

-   -   (d) reacting the enantiomerically enriched or enantiomerically        pure compound of Formula (IX-7), or a salt or isotopologue        thereof, with an acid chloride RCOCl, or an isotopologue        thereof, to form the enantiomerically enriched or        enantiomerically pure compound of Formula (I-b-7), or a salt or        isotopologue thereof.

In one embodiment, provided herein is a process for the preparation ofan enantiomerically enriched or enantiomerically pure compound ofFormula (I-b-8):

or a salt, solvate including a hydrate, stereoisomer, isotopologue, orpolymorph thereof, wherein:

-   -   R¹ is OMe enriched with 0, 1, 2, or 3 deuterium;    -   R² is OEt enriched with 0, 1, 2, 3, 4, or 5 deuterium;    -   R⁵ and R⁶ are independently hydrogen or deuterium; and    -   R is cyclopropyl enriched with 0, 1, 2, 3, 4, or 5 deuterium;        comprising the steps of    -   (a) reducing an enamine of Formula (II-b):

or a salt or isotopologue thereof, via hydrogenation with deuterium gas,in a solvent not containing exchangeable proton (including a solventcontaining exchangeable deuterium for proton-deuterium exchange, such asd₁-TFE), and in the presence of (1) a metal catalyst and a chiral ligandor (2) a chiral metal catalyst/ligand complex to form anenantiomerically enriched or enantiomerically pure aminosulfone ofFormula (III-8):

or a salt or isotopologue thereof;

-   -   (b) reacting the enantiomerically enriched or enantiomerically        pure aminosulfone of Formula (III-8), or a salt or isotopologue        thereof, with a compound of Formula (VI-a):

or a salt or isotopologue thereof, wherein R⁴ is (C₁-C₃)alkyl, and X ishalogen, to form an enantiomerically enriched or enantiomerically purecompound of Formula (VIII-8):

or a salt or isotopologue thereof;

-   -   (c) reducing the enantiomerically enriched or enantiomerically        pure compound of Formula (VIII-8), or a salt or isotopologue        thereof, to form an enantiomerically enriched or        enantiomerically pure compound of Formula (IX-8):

or a salt or isotopologue thereof; and

-   -   (d) reacting the enantiomerically enriched or enantiomerically        pure compound of Formula (IX-8), or a salt or isotopologue        thereof, with an acid chloride RCOCl, or an isotopologue        thereof, to form the enantiomerically enriched or        enantiomerically pure compound of Formula (I-b-8), or a salt or        isotopologue thereof.

With regard to the processes provided herein for the preparation of acompound of Formula (I-b-1), (I-b-2), (I-b-3), (I-b-4), (I-b-5),(I-b-6), (I-b-7), or (I-b-8), in one embodiment, R⁵ and R⁶ are bothhydrogen. In another embodiment, R⁵ and R⁶ are both deuterium. In yetanother embodiment, R⁵ is hydrogen and R⁶ is deuterium.

In one embodiment, an enantiomerically enriched or enantiomerically purecompound of Formula (I-b), or an isotopologue thereof, is a compound B:

or an isotopologue thereof.

4.2.3 Other Isotopologues

Although most embodiments and examples provided herein are directed toprocesses for the preparation of compounds enriched with one or moredeuterium in the

moiety of a compound provided herein, it is to be understood that thecorresponding compounds enriched with isotopes of carbon (e.g., ¹³C) andnitrogen (e.g., ¹⁵N) or enriched with deuterium at other moieties of acompound provided herein can be synthesized by the processes providedherein when the corresponding isotopically enriched starting materialsare used. For example, certain isotopically enriched intermediates havebeen reported in International Application Publication No.WO2012/097116.

In one embodiment, the processes provided herein are applied to thefollowing isopotologues of a compound of Formula (V):

In one embodiment, the processes provided herein are applied to thefollowing isopotologues of a compound of Formula (III):

A compound of Formula (I) prepared by the processes provided herein maybe subjected to further modifications known in the art to provideisotopologues of a compound of Formula (I). In one embodiment, asillustrated below, a compound of Formula (I) is subsequently subjectedto aromatic deuteration conditions to afford an aromatically deuteratedcompound of Formula (I).

In one embodiment, wherein R¹ is OMe, as illustrated below, a compoundof Formula (VIII) is subjected to demethylation, followed by acylationand methylation with isotopologues of MeI (e.g., CD₃I, ¹³CH₃I, or¹³CD₃I) to afford an isotopologue of a compound of Formula (I).

In one embodiment, wherein R¹ is OCD₃, as illustrated below, a4-(methoxy-d₃)-benzaldehyde is prepared by contacting a4-OH-benzaldehyde with D₃COSO₂OCD₃ in the presence of a base (e.g.,Cs₂CO₃) and in a solvent. In one embodiment, the solvent is acetone. Inanother embodiment, the solvent is a mixture of acetone and water. Inone embodiment, the solvent is 95:5 acetone/water. In one embodiment,the presence of water in the solvent suppresses formation of impuritiesresulted from aldo condensation. In one embodiment, the amount of Cs₂CO₃is between about 1 equiv. to about 3 equiv. to the 4-OH-benzaldehyde. Inone embodiment, the amount of Cs₂CO₃ is 1 equiv. to the4-OH-benzaldehyde.

4.2.4 Preparation of Aminosulfone Compounds

In one embodiment, provided herein is a process for the preparation ofan enantiomerically enriched or enantiomerically pure aminosulfonecompound of Formula (III):

or a salt, solvate including a hydrate, stereoisomer, isotopologue, orpolymorph thereof, wherein:

-   -   R¹ and R² are each independently hydrogen, halogen, substituted        or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted        (C₁-C₆)alkoxy, (C₃-C₁₈)cycloalkyl, (C₃-C₆)cycloalkoxy, cyano,        —CF₃, (C₃-C₁₈)cycloalkyl-(C₁-C₆)alkoxy, or an isotopologue        thereof;    -   R³ is (C₁-C₆)alkyl, or an isotopologue thereof; and    -   Y¹, Y², and Y³ are independently hydrogen or deuterium;        comprising the step of    -   (a) reducing an enamine of Formula (II):

or a salt or isotopologue thereof, via hydrogenation with hydrogen gasor deuterium gas, in a solvent, and in the presence of (1) a metalcatalyst and a chiral ligand or (2) a chiral metal catalyst/ligandcomplex to form an enantiomerically enriched or enantiomerically pureaminosulfone of Formula (III), or a salt or isotopologue thereof.

In one embodiment, provided herein is a process for the preparation ofan enantiomerically enriched or enantiomerically pure aminosulfonecompound of Formula (III):

or a salt, solvate including a hydrate, stereoisomer, isotopologue, orpolymorph thereof, wherein:

-   -   R¹ and R² are each independently hydrogen, halogen, substituted        or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted        (C₁-C₆)alkoxy, (C₃-C₁₈)cycloalkyl, (C₃-C₆)cycloalkoxy, cyano,        —CF₃, (C₃-C₁₈)cycloalkyl-(C₁-C₆)alkoxy, or an isotopologue        thereof;    -   R³ is (C₁-C₆)alkyl, or an isotopologue thereof; and    -   Y¹, Y², and Y³ are independently hydrogen or deuterium;    -   wherein not all of Y¹, Y², and Y³ are hydrogen;        comprising the step of    -   (a) reducing an enamine of Formula (II):

or a salt or isotopologue thereof, via hydrogenation with hydrogen gasor deuterium gas, in a solvent, and in the presence of (1) a metalcatalyst and a chiral ligand or (2) a chiral metal catalyst/ligandcomplex to form an enantiomerically enriched or enantiomerically pureaminosulfone of Formula (III), or a salt or isotopologue thereof,wherein deuterium gas or a solvent containing exchangeable deuterium forproton-deuterium exchange or both is used.

In one embodiment, provided herein is a process for the preparation ofan enantiomerically enriched or enantiomerically pure aminosulfonecompound of Formula (III):

or a salt, solvate including a hydrate, stereoisomer, isotopologue, orpolymorph thereof, wherein:

-   -   R¹ and R² are each independently hydrogen, halogen, substituted        or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted        (C₁-C₆)alkoxy, (C₃-C₁₈)cycloalkyl, (C₃-C₆)cycloalkoxy, cyano,        —CF₃, (C₃-C₁₈)cycloalkyl-(C₁-C₆)alkoxy, or an isotopologue        thereof;    -   R³ is (C₁-C₆)alkyl, or an isotopologue thereof;    -   Y¹ is hydrogen or deuterium; and    -   Y² and Y³ are both deuterium;        comprising the step of    -   (a) reducing an enamine of Formula (II):

or a salt or isotopologue thereof, via hydrogenation with hydrogen gasor deuterium gas, in a solvent containing exchangeable deuterium forproton-deuterium exchange, and in the presence of (1) a metal catalystand a chiral ligand or (2) a chiral metal catalyst/ligand complex toform an enantiomerically enriched or enantiomerically pure aminosulfoneof Formula (III), or a salt or isotopologue thereof.

Step (a) is as described herein and elsewhere above.

5. EXAMPLES

As used herein, the symbols and conventions used in these processes,schemes and examples, regardless of whether a particular abbreviation isspecifically defined, are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Specifically, butwithout limitation, the following abbreviations may be used in theexamples and throughout the specification: g (grams); mg (milligrams);mL (milliliters); μL (microliters); M (molar); mM (millimolar); μM(micromolar); eq. (equivalent); mmol (millimoles); Hz (Hertz); MHz(megahertz); hr or hrs (hour or hours); min (minutes); and MS (massspectrometry).

For all of the following examples, unless otherwise specified, standardwork-up and purification methods known to those skilled in the art canbe utilized. Unless otherwise specified, all temperatures are expressedin ° C. (degrees Centigrade). All reactions were conducted at roomtemperature unless otherwise noted. Synthetic methodologies illustratedherein are intended to exemplify the applicable chemistry through theuse of specific examples and are not indicative of the scope of thedisclosure.

Isotopically enriched analogs of the compounds provided herein maygenerally be prepared according synthetic routes known in the art,wherein one or more of the reagents, starting materials, precursors, orintermediates used is replaced by one or more isotopically enrichedreagents, starting materials, precursors, or intermediates. Isotopicallyenriched reagents, starting materials, precursors, or intermediates arecommercially available or may be prepared by routine procedures known toone of skill in the art. For example, the preparation of certainisotopically enriched intermediates have been reported in InternationalApplication Publication No. WO2012/097116.

Example 1 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethenamine(H—CH3-Compound C)

A slurry of dimethylsulfone (85 g, 903 mmol) in THF (480 ml) was treatedwith a 1.6M solution of n-butyllithium in hexane (505 ml, 808 mmol) at0-5° C. The resulting mixture was agitated for 1 hour then a solution of3-ethoxy-4-methoxybenzonitrile (80 g, 451 mmol) in THF (240 ml) wasadded at 0-5° C. The mixture was agitated at 0-5° C. for 0.5 hour,warmed to 25-30° C. over 0.5 hour and then agitated for 1 hour. Water(1.4 L) was added at 25-30° C. and the reaction mass was agitatedovernight at room temperature (20-30° C.). The solid was filtered andsubsequently washed with a 2:1 mixture of water:THF (200 ml), water (200ml) and heptane (2×200 ml). The solid was dried under reduced pressureat 40-45° C. to provide the product as a white solid (102 g, 83% yield);¹H NMR (DMSO-d₆) δ 1.34 (t, J=7.0 Hz, 3H), 2.99 (s, 3H), 3.80 (s, 3H),4.08 (q, J=7.0 Hz, 2H), 5.03 (s, 1H), 6.82 (s, 2H), 7.01 (d, J=8.5 Hz,1H), 7.09-7.22 (m, 2H).

Example 2 (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine(H—CH2-CH3-Compound D)

A solution of bis(1,5-cyclooctadiene)rhodium(I)trifluoromethanesulfonate (36 mg, 0.074 mmol) and(S)-1[(R)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine(40 mg, 0.074 mmol) in 25 mL of 2,2,2-trifluoroethanol was preparedunder nitrogen. To this solution was then charged1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethenamine (2.0 g, 7.4mmol). The resulting mixture was heated to 50° C. and hydrogenated under90 psig hydrogen pressure. After 18 h, the mixture was cooled to ambienttemperature and removed from the hydrogenator. The mixture wasevaporated and the residue was purified by chromatography on a C18reverse phase column using a water-acetonitrile gradient. Theappropriate fractions were pooled and evaporated to ˜150 mL. To thissolution was added brine (20 mL), and the resulting solution wasextracted with EtOAc (3×50 mL). The combined organic layers were dried(MgSO₄) and evaporated to provide the product as a white crystallinesolid (1.4 g, 70% yield); achiral HPLC (Hypersil BDS C₈, 5.0 μm, 250×4.6mm, 1.5 mL/min, 278 nm, 90/10 gradient to 80/20 0.1% aqueous TFA/MeOHover 10 min then gradient to 10/90 0.1% aqueous TFA/MeOH over the next15 min): 9.11 (99.6%); chiral HPLC (Chiralpak AD-H 5.0 μm Daicel,250×4.6 mm, 1.0 mL/min, 280 nm, 70:30:0.1 heptane-i-PrOH-diethylamine):7.32 (97.5%), 8.26 (2.47%); ¹H NMR (DMSO-d₆) δ 1.32 (t, J=7.0 Hz, 3H),2.08 (s, 2H), 2.96 (s, 3H), 3.23 (dd, J=3.6, 14.4 Hz, 1H), 3.41 (dd,J=9.4, 14.4 Hz, 1H), 3.73 (s, 3H), 4.02 (q, J=7.0 Hz, 2H), 4.26 (dd,J=3.7, 9.3 Hz, 1H), 6.89 (s, 2H), 7.02 (s, 1H); ¹³C NMR (DMSO-d₆) δ14.77, 41.98, 50.89, 55.54, 62.03, 63.68, 111.48, 111.77, 118.36,137.30, 147.93, 148.09.

Example 3(S)—N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide(H—CH2-CH3-Compound A)

N-(1,3-dioxo-1,3-dihydroisobenzofuran-4-yl)acetamide, which may beobtained via techniques known in the art,(S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine, andglacial acetic acid is refluxed overnight and then cooled to <50° C. Thesolvent is then removed in vacuo, and the residue is dissolved in ethylacetate. The resulting solution is washed with water, saturated aqueousNaHCO₃, brine, and dried over sodium sulphate. The solvent is evaporatedin vacuo, and the residue is recrystallized from a binary solventcontaining ethanol and acetone. The solid is isolated by vacuumfiltration and washed with ethanol. The product is then dried to affordH—CH2-CH3-Compound A.

Example 4(S)—N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide(H—CH2-CH3-Compound B)

A mixture of ethyl 2-(bromomethyl)-6-nitrobenzoate andH—CH2-CH3-Compound D, triethyl amine in DMF is heated to reflux. Thesolvent is removed in vacuo. The crude mixture is purified by columnchromatography to give(S)-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-7-nitroisoindolin-1-one.A mixture of(S)-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-7-nitroisoindolin-1-oneand Pd/C in ethyl acetate is shaken under hydrogen. The suspension isfiltered thru a pad of Celite. The solvent is removed in vacuo. Thecrude mixture is purified by column chromatography to give(S)-7-amino-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)isoindolin-1-one.

(S)—N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-3-oxoisoindolin-4-yl)cyclopropanecarboxamideis synthesized based upon the procedures described, for example, inExample 7 of U.S. Pat. No. 6,667,316, starting from(S)-7-amino-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)isoindolin-1-one.The product is further purified by column chromatography orcrystallization.

Example 5 D-CH2-CH3-Compound D

D-CH2-CH3-Compound D is prepared based on the routes described inExample 2, but using deuterium gas in place of hydrogen gas.

Example 6 D-CH2-CH3-Compound A

D-CH2-CH3-Compound A is prepared based on the routes described inExample 3, but using D-CH2-CH3-Compound D in place of H—CH2-CH3-CompoundD.

Example 7 D-CH2-CH3-Compound B

D-CH2-CH3-Compound B is prepared based on the routes described inExample 4, but using D-CH2-CH3-Compound D in place of H—CH2-CH3-CompoundD.

Example 8 H-CD2-CH3-Compound D

H-CD2-CH3-Compound D is prepared based on the routes described inExample 2, but using d¹-TFE in place of TFE as solvent.

Example 9 H-CD2-CH3-Compound A

H-CD2-CH3-Compound A is prepared based on the routes described inExample 3, but using H-CD2-CH3-Compound D in place of H—CH2-CH3-CompoundD.

Example 10 H-CD2-CH3-Compound B

H-CD2-CH3-Compound B is prepared based on the routes described inExample 4, but using H-CD2-CH3-Compound D in place of H—CH2-CH3-CompoundD.

Example 11 D-CD2-CH3-Compound D

D-CD2-CH3-Compound D is prepared based on the routes described inExample 2, but using deuterium gas in place of hydrogen gas and usingd¹-TFE in place of TFE as solvent.

Example 12 D-CD2-CH3-Compound A

D-CD2-CH3-Compound A is prepared based on the routes described inExample 3, but using D-CD2-CH3-Compound D in place of H—CH2-CH3-CompoundD.

Example 13 D-CD2-CH3-Compound B

D-CD2-CH3-Compound B is prepared based on the routes described inExample 4, but using D-CD2-CH3-Compound D in place of H—CH2-CH3-CompoundD.

Example 14 D-CD3-Compound C

D-CD3-Compound C is prepared based on the routes described in Example 1,but using CD₃SO₂CD₃ in place of CH₃SO₂CH₃.

Example 15 H—CH2-CD3-Compound D

H—CH2-CD3-Compound D is prepared based on the routes described inExample 2, but using D-CD3-Compound C in place of H—CH3-Compound C.

Example 16 H—CH2-CD3-Compound A

H—CH2-CD3-Compound A is prepared based on the routes described inExample 3, but using H—CH2-CD3-Compound D in place of H—CH2-CH3-CompoundD.

Example 17 H—CH2-CD3-Compound B

H—CH2-CD3-Compound B is prepared based on the routes described inExample 4, but using H—CH2-CD3-Compound D in place of H—CH2-CH3-CompoundD.

Example 18 D-CH2-CD3-Compound D

D-CH2-CD3-Compound D is prepared based on the routes described inExample 2, but using D-CD3-Compound C in place of H—CH3-Compound C andusing deuterium gas in place of hydrogen gas.

Example 19 D-CH2-CD3-Compound A

D-CH2-CD3-Compound A is prepared based on the routes described inExample 3, but using D-CH2-CD3-Compound D in place of H—CH2-CH3-CompoundD.

Example 20 D-CH2-CD3-Compound B

D-CH2-CD3-Compound B is prepared based on the routes described inExample 4, but using D-CH2-CD3-Compound D in place of H—CH2-CH3-CompoundD.

Example 21 H-CD2-CD3-Compound D

H-CD2-CD3-Compound D is prepared based on the routes described inExample 2, but using D-CD3-Compound C in place of H—CH3-Compound C andusing d¹-TFE in place of TFE as solvent.

Example 22 H-CD2-CD3-Compound A

H-CD2-CD3-Compound A is prepared based on the routes described inExample 3, but using H-CD2-CD3-Compound D in place of H—CH2-CH3-CompoundD.

Example 23 H-CD2-CD3-Compound B

H-CD2-CD3-Compound B is prepared based on the routes described inExample 4, but using H-CD2-CD3-Compound D in place of H—CH2-CH3-CompoundD.

Example 24 D-CD2-CD3-Compound D

D-CD2-CD3-Compound D is prepared based on the routes described inExample 2, but using D-CD3-Compound C in place of H—CH3-Compound C,using deuterium gas in place of hydrogen gas, and using d¹-TFE in placeof TFE as solvent.

Example 25 D-CD2-CD3-Compound A

D-CD2-CD3-Compound A is prepared based on the routes described inExample 3, but using D-CD2-CD3-Compound D in place of H—CH2-CH3-CompoundD.

Example 26 D-CD2-CD3-Compound B

D-CD2-CD3-Compound B is prepared based on the routes described inExample 4, but using D-CD2-CD3-Compound D in place of H—CH2-CH3-CompoundD.

Example 27 Preparation of 3-ethoxy-4-(d₃-methoxy)-benzaldehyde

Two batches of 3-ethoxy-4-(methoxy-d₃)-benzaldehyde were synthesizedusing the conditions shown below. The first batch was 10 g scale (basedon (CD₃)₂SO₄) and provided 13.9 g of product, area % 99.7%; and thesecond batch was 20 g scale and provided 28 g of product, area % 99.9%.The yields for both batches were quantitative.

A mixture of 3-ethoxy-4-hydroxybenzaldehyde (12.6 g, 76 mmol) and Cs₂CO₃(24.7 g, 75.9 mmol) in acetone was cooled in ice-water bath. (CD₃)₂SO₄(10.0 g, 75.9 mmol) was added and the reaction was allowed to warmslowly to room temperature and was stirred overnight. The reactionmixture was filtered through a pad of celite, the filtrate wasconcentrated to dryness to give a colorless liquid. The liquid wascooled to room temperature, forming a blue solid. The solid was driedunder vacuum at 40° C. providing 13.9 g of the product, in 100% yield;¹H NMR (d₆-DMSO) δ 1.35 (t, J=7.0 Hz, 3H), 4.09 (q, J=6.9 Hz, 2H), 7.17(d, J=8.3 Hz, 1H), 7.37 (d, J=1.7 Hz, 1H), 7.55 (dd, J=1.9, 8.1 Hz, 1H),9.83 (s, 1H).

Example 28 Preparation of 3-ethoxy-4-(d₃-methoxy)-benzonitrile

A mixture of hydroxylamine hydrochloride (12.3 g, 177 mmol) inacetonitrile (15 mL) was heated to 70° C. A solution ofethoxy-4-(d₃-methoxy)benzaldehyde (27.0 g, 147 mmol) in acetonitrile (40mL) was charged to the mixture and the batch was stirred at 70° C. for 4hours. The batch was heated to 85° C. for 1 hour and cooled to 20° C.The reaction mixture was evaporated to dryness and dissolved in ethylacetate (250 mL). The organic layer was washed with water (3×50 mL),brine (30 mL), dried with magnesium sulfate and filtered. The filtratewas evaporated to dryness and the residue was chromatographed (silicagel), eluting with hexane-ethyl acetate 5:1 providing 24.5 g of theproduct, in 92% yield; ¹H NMR (d₆-DMSO) δ 1.33 (t, J=7.0 Hz, 3H), 4.06(q, J=7.0 Hz, 2H), 7.11 (d, J=8.3 Hz, 1H), 7.30-7.49 (m, 2H).

Example 29 Preparation of d₃-enamine

A mixture of dimethylsulfone (5.22 g, 55.5 mmol) in THF (31 mL) wascooled to 0-5° C., and n-butyllithium (31.0 ml, 49.7 mmol) was added at0-5° C. After the addition was complete, the mixture was stirred at 0-5°C. for 1 hour and a solution of 3-ethoxy-4-methoxybenzonitrile-d₃ (5.00g 27.7 mmol) in THF (15 mL) was added, and the mixture was warmed toroom temperature. Water (85 mL) was charged at 20-30° C. and the batchwas stirred at 20° C. overnight. The precipitated solid was filtered,washed with 2:1 water:THF (12.5 mL), water (12.5 mL, 2.5×) and heptane(2×12.5 mL). The product was dried under vacuum at 40° C., providing 6.6g of product, in 87% yield; ¹H NMR (d₆-DMSO) δ 1.34 (t, J=7.0 Hz, 3H),2.99 (s, 3H), 4.08 (q, J=6.9 Hz, 2H), 5.02 (s, 1H), 6.81 (br, 2H), 7.00(d, J=8.5 Hz, 1H), 7.12 (d, J=2.1 Hz, 1H), 7.14-7.22 (m, 1H).

Example 30 Preparation of d₇-enamine

A mixture of d₆-dimethylsulfone (5.56 g, 55.5 mmol) and THF (30 mL) wascooled to 0-5° C., and n-butyllithium (31.0 mL, 49.7 mmol) was added at0-5° C. After addition was complete, the mixture was stirred at 0-5° C.for 1 hour and a solution of d₃-[3-ethoxy-4-methoxybenzonitrile] (5.00 g27.7 mmol) in THF (15 mL) was added, and the mixture was warmed up toroom temperature. Water (85 mL) was charged at 20-30° C. and the batchwas stirred at 20° C. overnight. The precipitated solid was filtered,washed with 2:1 water:THF (12.5 mL), water (12.5 mL, 2.5×) and heptane(2×12.5 mL). The product was dried under vacuum at 40° C., providing 6.5g of the product, in 84% yield; ¹H NMR (d₆-DMSO) δ 1.26-1.44 (m, 3H),4.08 (q, J=7.0 Hz, 2H), 6.95-7.07 (m, 1H), 7.09-7.27 (m, 2H).

Example 31 Preparation of d₃-aminosulfone N-acetyl-L-leucine salt

d₃-Enamine (2.0 g, 7.3 mmol) was added to a solution of Rh(cod)₂OTf (8.9mg, 0.018 mmol) and (S,R)-t-Bu-Josiphos (9.89 mg, 0.018 mmol) in2,2,2-trifluoroethanol (10 mL), and the resulting mixture washydrogenated under 50 psi hydrogen at 50° C. for 16 h. When the reactionwas complete, Ecosorb C-941 (0.2 g) was charged to flask and the mixturewas stirred at room temperature for 3 hours. The mixture was filteredthrough celite into a 50 mL jacket flask, the celite pad was washed with2,2,2-trifluoroethanol (2 mL). The batch was heated to 55° C. and asolution of (S)-2-acetamido-4-methylpentanoic acid (1.263 g, 7.29mmol)(N—Ac-Leu) in methanol (14 ml) was charged over 1 hour. The batchwas cooled to room temperature and filtered, washed with methanol (4 mL)and dried under vacuum, providing 2.6 g of the product, in 79% yield;HPLC (Hypersil BDS C₈, 5.0 μm, 250×4.6 mm, 1.5 mL/min, 278 nm, 90/10gradient to 80/20 0.1% aqueous TFA/MeOH over 10 min then gradient to10/90 0.1% aqueous TFA/MeOH over the next 15 min): 8.54 (99.8%); chiralHPLC (Chiralpak AD-H 5.0 μm Daicel, 250×4.6 mm, 1.0 mL/min, 280 nm,50:40:10 heptane-EtOH-i-PrOH): 6.94 (0.53%), 7.55 (99.47%); ¹H NMR(d₆-DMSO) δ 0.86 (dd, J=6.5, 14.1 Hz, 6H), 1.33 (t, J=6.9 Hz, 3H),1.42-1.54 (m, 2H), 1.61 (dd, J=6.9, 13.5 Hz, 1H), 1.83 (s, 3H), 2.94 (s,3H), 3.23-3.37 (m, 1H), 3.37-3.51 (m, 1H), 4.02 (q, J=7.0 Hz, 2H), 4.18(q, J=7.8 Hz, 1H), 4.29 (dd, J=4.1, 9.0 Hz, 1H), 6.89 (s, 2H), 7.03 (s,1H), 8.03 (d, J=8.1 Hz, 1H).

Example 32 Preparation of d₄-aminosulfone N-acetyl-L-leucine salt

d₃-Enamine- (3 g, 10.93 mmol) was added to a solution of Rh(cod)₂OTf (13mg, 0.027 mmol) and (S,R)-t-Bu-Josiphos (15 mg, 0.027 mmol) ind-2,2,2-trifluoroethanol (15 mL), and the resulting mixture was stirredunder 50 psi deuterium gas at 50° C. for 16 h. Then, Ecosorb C-941 (0.3g) was added and the mixture was stirred at room temperature for 3hours, and was then filtered through celite. The mixture was heated to55° C. and a solution of (S)-2-acetamido-4-methylpentanoic acid (1.89 g,10.9 mmol) (N—Ac-Leu) in methanol (21 ml) was added over 1 hour. Thebatch was held at 55° C. for 1 hour, cooled to 20° C. over 2 hours andthen stirred at 20° C. overnight. The precipitate was filtered, washedwith methanol (6 mL), and dried under vacuum, providing 4.3 g ofproduct, in 86% yield; HPLC (Hypersil BDS C₈, 5.0 μm, 250×4.6 mm, 1.5mL/min, 278 nm, 90/10 gradient to 80/20 0.1% aqueous TFA/MeOH over 10min then gradient to 10/90 0.1% aqueous TFA/MeOH over the next 15 min):7.28 (99.8%); chiral HPLC (Chiralpak AD-H 5.0 μm Daicel, 250×4.6 mm, 1.0mL/min, 280 nm, 50:40:10 heptane-EtOH-i-PrOH): 5.37 (0.08%), 5.92(99.92%); ¹H NMR (DMSO-d₆) δ 0.77-0.96 (m, 6H), 1.24-1.38 (m, 3H),1.40-1.53 (m, 2H), 1.55-1.74 (m, 1H), 1.75-1.91 (m, 3H), 2.87-3.02 (m,3H), 3.21-3.54 (m, 2H), 4.02 (q, J=7.0 Hz, 2H), 4.18 (q, J=7.7 Hz, 1H),6.81-6.96 (m, 2H), 7.03 (s, 1H), 8.04 (d, J=7.9 Hz, 1H).

Example 33 Preparation of d6-aminosulfone N-acetyl-L-leucine salt

d₃-Enamine (3.0 g, 10.93 mmol) was added to a solution of Rh(cod)₂OTf(13 mg, 0.027 mmol) and (S,R)-t-Bu-Josiphos (15 mg, 0.027 mmol) in2,2,2-trifluoroethanol (15 mL), and the resulting mixture was stirredunder 50 psi deuterium gas at 50° C. for 16 h. Then, Ecosorb C-941 (0.3g) was added and the mixture was stirred at room temperature for 3hours, and was then filtered through celite. The mixture was heated to55° C. and a solution of (S)-2-acetamido-4-methylpentanoic acid (1.89 g,10.9 mmol) (N—Ac-Leu) in methanol (24 ml) was added over 1 hour. Thebatch was held at 55° C. for 1 hour, cooled to 20° C. over 2 hours andthen stirred at 20° C. overnight. The precipitate was filtered, washedwith d-methanol (6 mL), and dried under vacuum, providing 4.2 g ofproduct, in 85% yield; HPLC (Hypersil BDS C₈, 5.0 μm, 250×4.6 mm, 1.5mL/min, 278 nm, 90/10 gradient to 80/20 0.1% aqueous TFA/MeOH over 10min then gradient to 10/90 0.1% aqueous TFA/MeOH over the next 15 min):7.03 (99.5%); chiral HPLC (Chiralpak AD-H 5.0 μm Daicel, 250×4.6 mm, 1.0mL/min, 280 nm, 50:40:10 heptane-EtOH-i-PrOH): 5.39 (0.48%), 5.92(99.52%); ¹H NMR (d₆-DMSO) δ 0.83-0.90 (m, 6H), 1.30-1.35 (t, J=7.0 Hz,3H), 1.45-1.50 (m, 2H), 1.60-1.64 (m, 1H), 1.83 (s, 3H), 2.94 (s, 3H),4.02 (q, J=7.0 Hz, 2H), 4.15-4.19 (m, 1H), 6.81-6.96 (m, 2H), 7.04 (s,1H), 8.03 (d, J=6.0 Hz, 1H).

Example 34 Preparation of d₉-aminosulfone N-acetyl-L-leucine salt

d₇-Enamine (4 g, 14.27 mmol) was added to a solution of Rh(cod)₂OTf (17mg, 0.036 mmol) and (S,R)-t-Bu-Josiphos (19 mg, 0.036 mmol) ind-2,2,2-trifluoroethanol (20 mL), and the resulting mixture was stirredunder 50 psi deuterium gas at 50° C. for 16 h. Then the mixture wascooled to room temperature. Ecosorb C-941 (0.4 g) was added and themixture was stirred at room temperature for 3 hours. The mixture wasfiltered through celite and was then heated to 55° C. and a solution ofd₂-(S)-2-acetamido-4-methylpentanoic acid (2.5 g, 14.3mmol)(d₂-N—Ac-Leu) in d-methanol (28 ml) was charged over 1 hour, andthen the mixture was cooled to room temperature. The precipitated solidwas filtered, washed with d-methanol (8 mL) and dried under vacuum,providing 5.6 g, in 85% yield; achiral HPLC (Hypersil BDS C₈, 5.0 μm,250×4.6 mm, 1.5 mL/min, 278 nm, 90/10 gradient to 80/20 0.1% aqueousTFA/MeOH over 10 min then gradient to 10/90 0.1% aqueous TFA/MeOH overthe next 15 min): 7.31 (99.9%); chiral HPLC (Chiralpak AD-H 5.0 μmDaicel, 250×4.6 mm, 1.0 mL/min, 280 nm, 50:40:10 heptane-EtOH-i-PrOH):5.39 (0.19%), 5.88 (99.8%); ¹H NMR (d₆-DMSO) d 0.87 (dd, J=6.5, 14.4 Hz,6H), 1.33 (t, J=7.0 Hz, 3H), 1.41-1.52 (m, 2H), 1.52-1.71 (m, 1H), 1.83(s, 3H), 4.02 (q, J=7.0 Hz, 2H), 4.12-4.24 (m, 1H), 6.89 (s, 2H),6.99-7.11 (m, 1H), 7.03 (s, 1H).

Example 35 Preparation of 3-(d₅-ethoxy)-4-(d₃-methoxy)-benzaldehyde

A mixture of 3,4-dihydroxybenzaldehyde (40 g, 290 mmol) and K₂CO₃ (40.0g, 290 mmol) in DMF (200 mL) was cooled to 0° C. and CD₃I (19.7 mL, 320mmol) was added over 4 h. The mixture was stirred at 0° C. for 16 h andthen was warmed to room temperature, and stirring proceeded for anadditional 20 h. The mixture was diluted with ethyl acetate (600 mL) andfiltered through a pad of Celite. The filtrate was concentrated to givea brown oil, which was then redissolved in EtOAc (600 mL). Water (200mL) was added and the pH was adjusted to pH˜3 by the addition of 1N HCl.The organic layer was separated and the aqueous phase was extracted withEtOAc (2×200 mL). The combined organic solution was dried (Na₂SO₄) andconcentrated. The crude material was purified by silica gel columnchromatography using a hexanes-ethyl acetate gradient. The product thusobtained was recrystallized from dichloromethane/hexanes to give 11.5 gof d₃-isovanillin (25.6%); ¹H NMR (CDCl₃) δ 5.74 (s, 1H), 6.97 (dd,J=6.3, 2.4 Hz, 1H), 7.42-7.45 (m, 2H), 9.98 (s, 1H); HPLC (WatersNova-pack C₁₈, 4.0 μm, 150×3.9 mm, 1.0 mL/min, 278 nm, 70/30 isocraticacetonitrile/water with 1% TFA, 15 min): 1.92 (98.4%).

To a mixture of thus formed d₃-isovanillin (11.0 g, 70.9 mmol), andK₂CO₃ (19.6 g, 142 mmol) in DMF (40 mL) was added d₅-ethyl iodide (6.80ml, 84.5 mmol) in dropwise fashion, and the mixture was stirred at rtfor 2 days. The reaction was quenched with 500 mL of ice-water. Theprecipitated product was collected by filtration and washed with water(100 mL). The product was dried under vacuum to provide 12.6 g (94%) ofproduc; ¹H NMR (CDCl₃) δ 6.97 (d, J=8.1 Hz, 1H), 7.40 (d, J=1.9 Hz, 1H),7.44 (dd J=8.1, 1.9 Hz, 1H), 9.84 (s, 1H); HPLC (Waters Nova-pack C₁₈,4.0 μm, 150×3.9 mm, 1.0 mL/min, 278 nm, 70/30 isocraticacetonitrile/water with 1% TFA, 15 min): 4.95 (99.8%).

Example 36 Preparation of 3-(d₅-ethoxy)-4-(d₃-methoxy)-benzonitrile

A mixture of hydroxylamine hydrochloride (5.4 g, 78 mmol) inacetonitrile (16 mL) was warmed to 72° C., and a solution ofd₈-3-ethoxy-4-methoxybenzaldehyde (12.2 g, 64.8 mmol) in acetonitrile(18 mL) was added. The mixture was stirred for 12 h at this temperatureand then cooled to room temperature. Water (70 mL) was added, and theproduct was collected by filtration and dried under vacuum to providethe desired product (11.8 g, 98%); ¹H NMR (CDCl₃) δ 6.89 (d J=8.4 Hz,1H), 7.06 (d, J=1.8 Hz, 1H), 7.26 (dd J=8.4, 1.8 Hz, 1H); HPLC (WatersNova-pack C₁₈, 4.0 μm, 150×3.9 mm, 1.0 mL/min, 278 nm, 70/30 isocraticacetonitrile/water with 1% TFA, 15 min): 7.74 (97.2%).

Example 37 Preparation of d₈-enamine

A mixture of dimethylsulfone (2.03 g, 21.6 mmol) in THF (15.9 mL) wascooled to 0° C., and n-butyllithium (12.1 mL, 19.3 mmol) was addeddropwise. The mixture was stirred at 0° C. for 1 h, and then a solutionof d₈-benzonitrile (2.0 g, 10.8 mmol) in THF (6.0 mL) was added over 30min. After completion of the addition, the mixture was warmed to 25-30°C. and stirred at that temperature for 3 h, and then water (25 mL) wasadded in dropwise fashion. The resulting slurry was stirred at 28° C.overnight and then cooled to 5° C. The precipitated product wascollected by filtration, washed with 2:1 water/THF (10 mL), water (2×10mL) and hexane (2×10 mL), and dried under vacuum to provide 2.4 g (82%);¹H NMR (CDCl₃) δ 2.99 (s, 3H), 3.32 (s, 2H), 6.81 (br, 2H), 7.00 (d,J=8.4 Hz, 1H), 7.12 (d, J=2.1 Hz, 1H,), 7.17 (dd J=8.4, 2.1 Hz, 1H,);HPLC (Hypersil BDS C₈, 5.0 μm, 250×4.6 mm, 1.5 mL/min, 278 nm, 90/10gradient to 80/20 0.1% aqueous TFA/MeOH over 10 min then gradient to10/90 0.1% aqueous TFA/MeOH over the next 15 min): 13.60 (99.0%).

Example 38 Preparation of d₁₂-enamine

A mixture of d₆-dimethylsulfone (4.33 g, 43.2 mmol) in THF (31.8 mL) wascooled to 0° C., and n-butyllithium (24.2 mL, 38.7 mmol) was added over1 h. The resulting mixture was stirred at 0° C. for 1 h. Then, asolution of d₈-benzonitrile (4.0 g, 21.6 mmol) in THF (11.5 mL) wasadded over 30 min and then the mixture was warmed to 25-30° C. over 30min. The mixture was stirred at this temperature for 3 h then deuteriumoxide (41.2 mL, 2290 mmol) was added dropwise. Organic solvent wasevaporated under reduced pressure until precipitate formed. Theprecipitated product was filtered, washed with MTBE (10 mL, and driedunder vacuum to afford 4.3 g of the product, in 70% yield; ¹H NMR(CDCl₃) δ 7.00 (d J=8.4 Hz, 1H,), 7.12 (d, J=1.8 Hz, 1H), 7.17 (dd,J=8.4, 2.1 Hz, 1H,); HPLC (Hypersil BDS C₈, 5.0 μm, 250×4.6 mm, 1.5mL/min, 278 nm, 90/10 gradient to 80/20 0.1% aqueous TFA/MeOH over 10min then gradient to 10/90 0.1% aqueous TFA/MeOH over the next 15 min):13.58 (97.58%).

Example 39 Preparation of d₉-aminosulfone N-acetyl-L-leucine salt

d₈-Enamine (2.0 g, 7.3 mmol) was added to a solution of Rh(cod)₂OTf (8.9mg, 0.018 mmol) and (S,R)-t-Bu-Josiphos (9.89 mg, 0.018 mmol) in2,2,2-trifluoroethanol (10 mL), and the resulting mixture was stirredunder 50 psi deuterium at 50° C. for 16 h. When the reaction wascomplete, Ecosorb C-941 (0.2 g) was charged to flask and the mixture wasstirred at room temperature for 3 hours. The mixture was filteredthrough celite into a 50 mL jacket flask, the celite pad was washed with2,2,2-trifluoroethanol (2 mL). The batch was heated to 55° C. and asolution of (S)-2-acetamido-4-methylpentanoic acid (1.89 g, 10.9 mmol)(N—Ac-Leu) in methanol (24 ml) was added over 1 hour. The batch wascooled to room temperature and filtered, washed with methanol (2×10 mL)and dried under vacuum, providing 3.3 g of the product, in 68% yield;HPLC (Hypersil BDS C₈, 5.0 μm, 250×4.6 mm, 1.5 mL/min, 278 nm, 90/10gradient to 80/20 0.1% aqueous TFA/MeOH over 10 min then gradient to10/90 0.1% aqueous TFA/MeOH over the next 15 min): 6.61 (99.44%); chiralHPLC (Chiralpak AD-H 5.0 μm Daicel, 250×4.6 mm, 1.0 mL/min, 280 nm,50:40:10 heptane-EtOH-i-PrOH): 5.51 (0.29%), 5.82 (99.71%); ¹H NMR(d₆-DMSO) δ 0.86 (dd, J=7.5, 15.0 Hz, 6H), 1.45-1.50 (m, 2H), 1.58-1.67(m, 1H), 1.83 (s, 3H), 4.18 (m, 1H), 6.89 (s, 2H), 7.03 (s, 1H), 8.04(d, J=9.0 Hz, 1H).

Example 40 Preparation of d₁₄-aminosulfone N-acetyl-L-leucine salt

d₁₂-Enamine (3 g, 14.27 mmol) was added to a solution of Rh(cod)₂OTf (12mg, 0.036 mmol) and (S,R)-t-Bu-Josiphos (14 mg, 0.036 mmol) ind-2,2,2-trifluoroethanol (15 mL), and the resulting mixture was stirredunder 50 psi deuterium gas at 50° C. for 40 h. Then the mixture wascooled to room temperature. Ecosorb C-941 (0.4 g) was added and themixture was stirred at room temperature for 3 hours. The mixture wasfiltered through celite and was then heated to 55° C. and a solution of(S)-2-acetamido-4-methylpentanoic acid (2.5 g, 14.3 mmol) (N—Ac-Leu) ind-methanol (28 ml) was charged over 1 hour, and then the mixture wascooled to room temperature. The precipitated solid was filtered, washedwith d-methanol (8 mL) and dried under vacuum, providing 5.6 g, in 85%yield; achiral HPLC (Hypersil BDS C₈, 5.0 μm, 250×4.6 mm, 1.5 mL/min,278 nm, 90/10 gradient to 80/20 0.1% aqueous TFA/MeOH over 10 min thengradient to 10/90 0.1% aqueous TFA/MeOH over the next 15 min): 7.31(99.9%); chiral HPLC (Chiralpak AD-H 5.0 μm Daicel, 250×4.6 mm, 1.0mL/min, 280 nm, 50:40:10 heptane-EtOH-i-PrOH): 5.39 (0.19%), 5.88(99.8%); ¹H NMR (d₆-DMSO) d 0.87 (dd, J=6.5, 14.4 Hz, 6H), 1.33 (t,J=7.0 Hz, 3H), 1.41-1.52 (m, 2H), 1.52-1.71 (m, 1H), 1.83 (s, 3H), 4.02(q, J=7.0 Hz, 2H), 4.12-4.24 (m, 1H), 6.89 (s, 2H), 6.99-7.11 (m, 1H),7.03 (s, 1H).

Example 41 Preparation of d₃-Compound A

To a slurry of d₃aminosulfone leucine salt (2.2 g, 4.89 mmol) indichloromethane (20 mL) was charged 17% aqueous NaOH (2.2 mL). Themixture was stirred for 5 minutes at room temperature, and then theorganic layer was dried (MgSO₄) and evaporated. To the residue was addedTHF (13.2 mL), acetic acid (3.27 g, 57.3 mmol) andN-(1,3-dioxo-1,3-dihydroisobenzofuran-4-yl)acetamide (1.00 g, 4.89mmol). The resulting mixture was heated at 70° C. for 24 hours. Thebatch was cooled to 35° C., THF (12 mL) and iPrOAc (24 mL) were added,the reaction mixture was washed with 10% NaH₂PO₄ solution (3×7 mL), andwater (3×7 mL), and was evaporated to dryness. To the residue was addediPrOAc (3×20 mL), and the mixture was evaporated to dryness. The residuewas dissolved in iPrOAc (9 mL) and the product was precipitated byadding MTBE (13 mL) slowly. The precipitate was filtered, washed withMTBE (4.4 mL) and dried under vacuum. The crude product wasrecrystallized in acetone-EtOH (7 mL: 22 mL), providing 1.7 g of theproduct, in 79% yield; UPLC (BEH C₁₈, 1.7 μm, 2.1×50 mm, 0.6 mL/min, 230nm, 95/5 gradient to 15/85 0.06% aqueous TFA/Acetonitrile (0.06% TFA)over 5 min): 2.60 (99.9%); chiral HPLC (Chiralpak AD-H 5.0 μm Daicel,250×4.6 mm, 1.0 mL/min, 280 nm, 70:30 heptane-EtOH): 13.32 (0.51%),15.30 (99.49%); ¹H NMR (d₆-DMSO) δ 1.32 (t, J=6.9 Hz, 3H), 2.19 (s, 3H),3.02 (s, 3H), 4.02 (q, J=7.0 Hz, 2H), 4.09-4.23 (m, 1H), 4.35 (dd,J=10.7, 14.3 Hz, 1H), 5.78 (dd, J=4.2, 10.4 Hz, 1H), 6.88-7.03 (m, 2H),7.07 (d, J=1.7 Hz, 1H), 7.57 (d, J=7.2 Hz, 1H), 7.79 (t, J=7.8 Hz, 1H),8.44 (d, J=8.3 Hz, 1H), 9.72 (s, 1H); ¹³C NMR (d₆-DMSO) δ 14.63, 24.15,41.03, 47.16, 52.87, 63.87, 111.79, 112.42, 116.66, 118.18, 119.71,126.10, 129.42, 131.33, 135.89, 136.48, 147.86, 148.91, 166.89, 167.80,169.21; Anal. (C₂₂H₂₁D₃N₂O₇S) C, H, N. Calcd C, 57.00; H, 5.22; N, 6.04.Found C, 57.15; H, 5.51; N, 6.04.

Example 42 Preparation of d₇-Compound A

To slurry of aminosulfone leucine salt (3 g, 6.64 mmol) indichloromethane (30 mL) was added 17% aqueous NaOH (3 mL). The mixturewas stirred for 5 minutes and the organic layer was dried (MgSO₄) andevaporated. To the residue was added THF (18 mL), d1-acetic acid (4.75g, 78 mmol) and d₃-N-(1,3-dioxo-1,3-dihydroisobenzofuran-4-yl)acetamide(1.38 g, 6.64 mmol). The resulting mixture was heated at 72° C. for 24hours. Then the mixture was cooled to 35° C., THF (18 mL) and iPrOAc (36mL) were added, and the reaction mixture was washed with 10% NaH₂PO₄solution (3×9 mL), and water (3×9 mL), and the organic phase wasevaporated to dryness. To the residue was added i-PrOAc (3×30 mL), andthe mixture was evaporated to dryness. The residue was dissolved ini-PrOAc (12 mL) and the product was precipitated by adding MTBE (18 mL)slowly. The precipitate was filtered, washed with MTBE (6 mL) and driedunder vacuum. The crude product was recrystallized in acetone-EtOH (9mL:28 mL), providing 2 g of the product, in 75% yield; UPLC (BEH C₁₈,1.7 μm, 2.1×50 mm, 0.6 mL/min, 230 nm, 95/5 gradient to 15/85 0.06%aqueous TFA/Acetonitrile (0.06% TFA) over 5 min): 2.54 (99.3%); chiralHPLC (Chiralpak AD-H 5.0 μm Daicel, 250×4.6 mm, 1.0 mL/min, 280 nm,70:30 heptane-EtOH): 12.86 (0.34%), 14.61 (99.66%); ¹H NMR (d₆-DMSO) δ1.31 (t, J=6.9 Hz, 3H), 2.89-3.16 (m, 3H), 4.01 (q, J=6.9 Hz, 2H), 4.12(d, J=14.4 Hz, 1H), 4.27-4.44 (m, 1H), 6.78-7.03 (m, 2H), 7.06 (s, 1H),7.56 (d, J=7.2 Hz, 1H), 7.78 (t, J=7.8 Hz, 1H), 8.43 (d, J=8.3 Hz, 1H),9.70 (s, 1H); ¹³C NMR (d₆-DMSO) δ 14.63, 41.03, 52.80, 63.87, 111.69,111.79, 112.43, 116.66, 118.15, 119.72, 126.08, 129.27, 129.36, 131.32,135.87, 136.46, 147.85, 148.93, 166.88, 167.78, 169.24; Anal.(C₂₂H₁₇D₇N₂O₇S) C, H, N. Calcd C, 56.51; H, 5.17; N, 5.99. Found C,56.58; H, 5.12; N, 5.95.

Example 43 Preparation of d₉-Compound A

To slurry of aminosulfone leucine salt (3.0 g, 6.6 mmol) indichloromethane (30 mL) was added 17% aqueous NaOH (3 mL). The mixturewas stirred for 5 minutes and the organic layer was dried (MgSO₄) andevaporated. To the residue was added THF (18 mL), d₁-acetic acid (4.74g, 78 mmol) and d₃-N-(1,3-dioxo-1,3-dihydroisobenzofuran-4-yl)acetamide(1.38 g, 6.63 mmol). The resulting mixture was heated at 73° C. for 24hours, and then the mixture was cooled to 35° C. THF (18 mL) and i-PrOAc(36 mL) were added, and the mixture was washed with 10% NaH₂PO₄ solution(3×9 mL), and water (3×9 mL), and the organic phase was evaporated todryness. To the residue was added i-PrOAc (3×30 mL), and the mixture wasevaporated to dryness. The residue was dissolved in i-PrOAc (12 mL) andthe product was precipitated by adding MTBE (18 mL) slowly. Theprecipitate was filtered, washed with MTBE (6 mL) and dried undervacuum. The crude product was recrystallizated in acetone-EtOH (9 mL:28mL), providing 2.0 g of the product, in 69% yield; UPLC (BEH C₁₈, 1.7μm, 2.1×50 mm, 0.6 mL/min, 230 nm, 95/5 gradient to 15/85 0.06% aqueousTFA/Acetonitrile (0.06% TFA) over 5 min): 2.54 (99.9%); chiral HPLC(Chiralpak AD-H 5.0 μm Daicel, 250×4.6 mm, 1.0 mL/min, 280 nm, 70:30heptane-EtOH): 12.52 (0.32%), 14.21 (99.68%); ¹H NMR (d₆-DMSO) δ 1.32(t, J=7.0 Hz, 3H), 2.96-3.06 (m, 3H), 4.02 (d, J=7.0 Hz, 2H), 6.90-7.03(m, 2H), 7.05-7.12 (m, 1H), 7.57 (d, J=6.8 Hz, 1H), 7.69-7.92 (m, 1H),8.44 (d, J=8.1 Hz, 1H), 9.71 (s, 1H); ¹³C NMR (d₆-DMSO) δ 14.63, 41.00,52.57, 63.87, 111.69, 111.79, 112.42, 116.66, 118.15, 119.71, 126.08,129.35, 131.33, 135.87, 136.46, 147.85, 148.93, 166.88, 167.78, 169.25;Anal. (C₂₂H₁₅D₉N₂O₇S) C, H, N. Calcd C, 56.27; H, 5.15; N, 5.97. FoundC, 56.34; H, 5.16; N, 5.93.

Example 44 Preparation of d₉-Compound A

To a slurry of aminosulfone leucine salt (2.5 g, 5.44 mmol) indichloromethane (25 mL) was added 17% aqueous NaOH (2.5 mL). The mixturewas stirred for 5 minutes and the organic layer was dried (MgSO₄) andevaporated under vacuum. To the residue was added THF (15 mL), d₆-aceticacid (4.1 g, 63.6 mmol) andN-(1,3-dioxo-1,3-dihydroisobenzofuran-4-yl)acetamide (1.12 g, 5.44mmol). The resulting mixture was heated at 70° C. for 24 hours, and thenthe mixture was cooled to 35° C. THF (15 mL) and iPrOAc (30 mL) wereadded, and the mixture was washed with 10% NaH₂PO₄ solution (3×7.5 mL),and water (3×7.5 mL), and the organic phase was evaporated to dryness.To the residue was added i-PrOAc (3×20 mL), and the mixture wasevaporated to dryness. The residue was dissolved in i-PrOAc (10 mL) andthe product was precipitated by adding MTBE (15 mL) slowly. Theprecipitate was filtered, washed with MTBE (5 mL) and dried undervacuum. The crude product was recrystallized in acetone-EtOH (7.6 mL: 24mL), providing 1.85 g of the product, in 76% yield; UPLC (BEH C₁₈, 1.7μm, 2.1×50 mm, 0.6 mL/min, 230 nm, 95/5 gradient to 15/85 0.06% aqueousTFA/Acetonitrile (0.06% TFA) over 5 min): 2.55 (99.7%); chiral HPLC(Chiralpak AD-H 5.0 μm Daicel, 250×4.6 mm, 1.0 mL/min, 280 nm, 70:30heptane-EtOH): 13.04 (0.43%), 14.90 (99.57%); ¹H NMR (d6-DMSO) δ 1.32(t, J=6.9 Hz, 3H), 2.19 (s, 3H), 4.02 (q, J=6.9 Hz, 2H), 6.86-7.03 (m,2H), 7.03-7.19 (m, 1H), 7.57 (d, J=7.2 Hz, 1H), 7.79 (t, J=7.8 Hz, 1H),8.44 (d, J=8.3 Hz, 1H), 9.71 (s, 1H); ¹³C NMR (d₆-DMSO) δ 14.63, 24.15,63.87, 111.69, 111.79, 112.43, 116.66, 118.16, 119.72, 126.08, 129.26,129.35, 131.33, 135.88, 136.49, 147.86, 148.93, 166.89, 167.80, 169.20;Anal. (C₂₂H₁₅D₉N₂O₇S) C, H, N. Calcd C, 56.27; H, 5.15; N, 5.97. FoundC, 56.58; H, 5.12; N, 5.95.

Example 45 Preparation of d₁₂-Compound A

To slurry of aminosulfone leucine salt (2.3 g, 5.2 mmol) indichloromethane (23 mL) was added 17% aqueous NaOH (2.3 mL). The mixturewas stirred for 5 minutes and the organic layer was dried (MgSO₄) andevaporated under vacuum. To the residue was added THF (14 mL), d-aceticacid (3.74 g, 61.2 mmol) andd₃-N-(1,3-dioxo-1,3-dihydroisobenzofuran-4-yl)acetamide (1.09 g, 5.23mmol). The resulting mixture was heated at 73° C. for 43 hours, and thenthe mixture was cooled to 35° C. THF (12 mL) and i-PrOAc (24 mL) wereadded, and the reaction mixture was washed with 10% NaH₂PO₄ solution(3×7 mL) and water (3×7 mL), and the organic phase was evaporated todryness. To the residue was added i-PrOAc (3×20 mL), and the mixture wasevaporated to dryness. The residue was dissolved in i-PrOAc (9 mL) andthe product was precipitated by adding MTBE (14 mL) slowly. Theprecipitate was filtered, washed with MTBE (5 mL) and dried undervacuum. The crude product was recrystallizated in acetone-EtOH (9 mL:28mL), providing 1.66 g of product, in 73% yield; UPLC (BEH C₁₈, 1.7 μm,2.1×50 mm, 0.6 mL/min, 230 nm, 95/5 gradient to 15/85 0.06% aqueousTFA/Acetonitrile (0.06% TFA) over 5 min): 2.53 (100%); chiral HPLC(Chiralpak AD-H 5.0 μm Daicel, 250×4.6 mm, 1.0 mL/min, 280 nm, 70:30heptane-EtOH): 12.06 (0.29%), 13.62 (99.71%); ¹H NMR (d₆-DMSO) δ 3.01(s, 3H), 4.13 (d, J=14.4 Hz, 1H), 4.25-4.43 (m, 1H), 6.79-7.03 (m, 2H),7.03-7.14 (m, 1H), 7.56 (d, J=6.6 Hz, 1H), 7.72-7.86 (m, 1H), 8.43 (d,J=8.3 Hz, 1H), 9.70 (s, 1H); ¹³C NMR (d₆-DMSO) δ 41.05, 47.16, 52.81,111.50, 111.69, 111.79, 112.41, 116.66, 118.16, 119.70, 126.08, 129.27,129.38, 131.33, 135.88, 136.48, 142.54, 147.88, 148.93, 166.89, 167.78,169.25; Anal. (C₂₂H₁₂D₁₂N₂O₇S) C, H, N. Calcd C, 55.91; H, 5.12; N,5.93. Found C, 56.10; H, 5.03; N, 6.05.

Example 46 Preparation of d₁₇-Compound A

To slurry of aminosulfone leucine salt (3.0 g, 6.6 mmol) indichloromethane (30 mL) was added 17% aqueous NaOH (3 mL). The mixturewas stirred for 5 minutes and the organic layer was dried (MgSO₄) andevaporated. To the residue was added THF (18 mL), d₁-acetic acid (4.74g, 78 mmol) and d₃-N-(1,3-dioxo-1,3-dihydroisobenzofuran-4-yl)acetamide(1.38 g, 6.63 mmol). The resulting mixture was heated at 73° C. for 40hours, and then the mixture was cooled to 35° C. i-PrOAc (18 mL) wasadded, and the mixture was washed with 10% NaH₂PO₄ solution (3×10 mL),and water (10 mL), and the organic phase was evaporated to dryness. Tothe residue was added i-PrOAc (3×30 mL), and the mixture was evaporatedto dryness. The residue was dissolved in i-PrOAc (12 mL) and the productwas precipitated by adding MTBE (18 mL) slowly. The precipitate wasfiltered, washed with MTBE (10 mL) and dried under vacuum. The crudeproduct was recrystallizated in acetone-EtOH (9 mL: 28 mL), providing1.9 g of the product, in 67% yield; UPLC (BEH C₁₈, 1.7 μm, 2.1×50 mm,0.6 mL/min, 230 nm, 95/5 gradient to 15/85 0.06% aqueousTFA/Acetonitrile (0.06% TFA) over 5 min): 2.53 (99.9%); chiral HPLC(Chiralpak AD-H 5.0 μm Daicel, 250×4.6 mm, 1.0 mL/min, 280 nm, 70:30heptane-EtOH): 12.32 (0.64%), 14.08 (99.16%); ¹H NMR (d₆-DMSO) δ6.92-6.99 (m, 2H), 7.07-7.08 (m, 1H), 7.57 (d, J=6.8 Hz, 1H), 7.76-7.81(m, 1H), 8.45 (d, J=8.1 Hz, 1H), 9.71 (s, 1H); ¹³C NMR (d₆-DMSO) δ111.79, 112.41, 116.65, 118.15, 119.68, 126.05, 129.35, 131.33, 135.87,136.49, 147.89, 148.93, 166.88, 167.78, 169.25; Anal. (C₂₂H₇D₁₇N₂O₇S) C,H, N. Calcd C, 55.31; H, 5.06; N, 5.86. Found C, 55.43; H, 4.98; N,5.81.

Example 47 Preparation of 3-ethoxy-4-(methoxy-d₃)-benzaldehyde

The synthesis of 3-ethoxy-4-(methoxy-d₃)-benzaldehyde was performedaccording to the scheme above. Reaction conditions were screened and theresults are summarized in Table 1. When acetone was used as the solvent,and about 1.5 equiv. of Cs₂CO₃ was used, significant impurity formationwas observed to the extent of ˜40 Area %. LCMS and NMR indicated theside products derived from aldol condensation of the solvent acetonewith the product aldehyde. LCMS showed the reaction was complete after1.5 hours, at which time there was very little side product formation;impurities formed with extended reaction time. The formation of theimpurities was suppressed in the presence of water.

TABLE 1 Reaction condition screening-methylation of3-ethoxy-4-hydroxybenzaldehyde % product % side product % product % sideproduct % product, % side product Reaction Solvent Cs₂CO₃ (eq.) 1 h 1 h6 h 6 h 21 h 21 h 1 acetone 1.53 100 0 75 25 50 50 2 acetone + 1.53 1000 100 0 100 0 5% water 3 acetone 1  92 0 97 0 100 0 4 DMF 1.53 ND ND NDND 100 0

Example 48 Determination of Isotopic Enrichment

Isotopic enrichment may be confirmed and quantified by mass spectrometryand/or NMR, including, for example, proton-NMR; carbon-13 NMR; ornitrogen-15 NMR.

Isotopic enrichment may also be confirmed by single-crystal neutrondiffraction. For example, the isotopic ratio at a particularhydrogen/deuterium position in a deuterated compound can be determinedusing single-crystal neutron diffraction. Neutron diffraction isadvantageous because neutrons are scattered by the nucleus of an atom,therefore allowing for discrimination between isotopes, such as hydrogenand deuterium, that differ in the number of neutrons in the nucleus.

A single crystal of suitable size and quality comprising the deuteratedcompound is grown using standard methods of crystal growth. Forsingle-crystal neutron diffraction experiments, crystals of severalcubic millimeters are generally required for suitable data collection. Aminimum size for a single crystal is typically about 1 cubic millimeter.Suitable single crystals are obtained by dissolving the deuteratedcompound in a solvent with appreciable solubility, then slowlyevaporating or cooling the solution to yield crystals of suitable sizeand quality. Alternatively, suitable single crystals are obtained bydissolving the deuterated compound in a solvent with appreciablesolubility, then slowly diffusing into the solution of antisolvent(i.e., a solvent in which the deuterated compound is not appreciablysoluble) to yield crystals of suitable size and quality. These and othersuitable methods of crystal growth are known in the art and aredescribed, e.g., in George H. Stout & Lyle H. Jensen, X-Ray StructureDetermination: A Practical Guide 74-92 (John Wiley & Sons, Inc. 2nd ed.1989) (the entirety of which is incorporated herein).

After isolating a suitable single crystal comprising the deuteratedcompound, the crystal is mounted in a neutron beam, neutron diffractiondata is collected, and the crystal structure is solved and refined.Different neutron sources can be used, including steady-state sourcesand pulsed spallation sources. Examples of steady-state sources includethe Grenoble ILL High Flux Reactor (Grenoble, France) and the Oak RidgeHigh Flux Isotope Reactor (Oak Ridge, Tenn.). Examples of pulsedspallation sources include ISIS, the spallation neutron source atRutherford Appleton Laboratory (Oxfordshire, UK); the Intense PulsedNeutron Source (IPNS) at Argonne National Laboratory (Argonne, Ill.),the Los Alamos Neutron Science Center (LANSCE) at Los Alamos NationalLaboratory (Los Alamos, N. Mex.), and the Neutron Science Laboratory(KENS) at KEK (Tsukuba, Ibaraki, Japan).

For a steady-state neutron source, four-circle diffractometer techniquesare used with a monochromatic beam and a single detector, rotating thecrystal and detector to measure each reflection sequentially.Diffractometer control software and step-scanning methods for intensityextraction can be adopted from routine four-circle X-ray diffractometrymethods. One or more area detectors, including area detector arrays, mayalternatively be used to increase the region of reciprocal spaceaccessed in a single measurement. A broad band (white) beam used with anarea detector allows for Laue or quasi-Laue diffraction with astationary crystal and detector.

For a pulse source with a white neutron beam, time-of-flight Lauediffraction techniques are used, which allow for the determination ofthe velocity, energy, and wavelength of each neutron detected. Thisapproach combines wavelength sorting with large area position-sensitivedetectors, and allows for fixed scattering geometries (i.e., astationary crystal and detector). Pulse source data collected in thisfashion allows for rapid collection of data sets and good accuracy andprecision in standard structural refinements. Additional detailsregarding steady-state and pulse source neutron diffraction experimentsare well known in the art. See, e.g., Chick C. Wilson, Neutron SingleCrystal Diffraction, 220 Z. Kristallogr. 385-98 (2005) (incorporated byreference herein in its entirety).

Crystal structure data, including particular isotopic ratios, areobtained from neutron diffraction data following routine structuresolution and refinement processes. Structure solution is carried outusing one of several methods, including direct methods and Pattersonmethods. For convenience, atomic coordinates from prior single crystalX-ray diffraction experiments may be used as a starting point forstructure refinement using neutron diffraction data; this approachpermits additional refinement of atomic positions, including hydrogenand deuterium positions. Refinement is conducted using full-matrixleast-squares methods to achieve optimal agreement between the observeddiffraction intensities and those calculated from the structural model.Ideally, full anisotropic refinement is carried out on all atoms,including the H/D atomic positions of interest. Data collection,structure solution and structure refinement methods, both for X-ray andneutron diffraction data, are well known in the art. See, e.g., Chick C.Wilson, Single Crystal Neutron Diffraction from Molecular Materials(World Scientific Publishing Co. 2000); George H. Stout & Lyle H.Jensen, X-Ray Structure Determination: A Practical Guide (John Wiley &Sons, Inc. 2nd ed. 1989) (both of which are incorporated herein in theirentireties).

The isotopic ratio for a particular position on a deuterated compound iscalculated by examining the neutron scattering cross sections for theH/D atomic position of interest. The scattering cross section isobtained as part of the refinement process discussed above. An exampleof determining the isotopic ratio for a partially deuterated compound isprovided by G. A. Jeffrey et al., Neutron Diffraction Refinement ofPartially Deuterated β-D-Arabinopyranose and α-L-Xylopyranose at 123 K,B36 Acta Crystallographica 373-77 (1980) (incorporated by referenceherein in its entirety). Jeffrey et al. used single-crystal neutrondiffraction to determine the percentage deuterium substitution forhydroxyl groups on two sugar compounds of interest. Employing themethods discussed by Jeffrey et al., one may similarly ascertain theisotopic ratio for a particular H/D position on a deuterated compound.

The examples set forth above are provided to give those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the claimed embodiments, and are not intended to limit thescope of what is disclosed herein. Modifications that are obvious topersons of skill in the art are intended to be within the scope of thefollowing claims. All publications, patents, and patent applicationscited in this specification are incorporated herein by reference as ifeach such publication, patent or patent application were specificallyand individually indicated to be incorporated herein by reference.

What is claimed is:
 1. A process for the preparation of anenantiomerically enriched or enantiomerically pure aminosulfone compoundof Formula (III):

or a salt stereoisomer, or isotopologue thereof, wherein: R¹ and R² areeach independently hydrogen, halogen, substituted or unsubstituted(C₁-C₆)alkyl, substituted or unsubstituted (C₁-C₆)alkoxy,(C₃-C₁₈)cycloalkyl, (C₃-C₆)cycloalkoxy, cyano, —CF₃,(C₃-C₁₈)cycloalkyl-(C₁-C₆)alkoxy, or an isotopologue thereof; R³ is(C₁-C₆)alkyl, or an isotopologue thereof; Y¹ is hydrogen or deuterium;and Y² and Y³ are both hydrogen or both deuterium; wherein not all ofY¹, Y², and Y³ are hydrogen; comprising the step of (a) reducing anenamine of Formula (II):

or a salt or isotopologue thereof, via hydrogenation with hydrogen gasor deuterium gas, in a solvent, and in the presence of (1) a metalcatalyst and a chiral ligand or (2) a chiral metal catalyst/ligandcomplex to form an enantiomerically enriched or enantiomerically pureaminosulfone of Formula (III), or a salt or isotopologue thereof,wherein deuterium gas or a solvent containing exchangeable deuterium forproton-deuterium exchange or both is used.
 2. The process of claim 1,wherein the enamine of Formula (II), or a salt or isotopologue thereof,is synthesized by reacting a nitrile of Formula (IV):

or an isotopologue thereof, with LiCH₂SO₂R³, or an isotopologue thereof.3. The process of claim 1, wherein R¹ and R² are substituted orunsubstituted (C₁-C₆)alkoxy, or an isotopologue thereof.
 4. The processof claim 3, wherein R¹ is OMe enriched with 0, 1, 2, or 3 deuterium, andR² is OEt enriched with 0, 1, 2, 3, 4, or 5 deuterium.
 5. The process ofclaim 4, wherein R¹ is OCD₃, and R² is OEt.
 6. The process of claim 4,wherein R¹ is OCD₃, and R² is OCD₂CD₃.
 7. The process of claim 1,wherein R³ is Me enriched with 0, 1, 2, or 3 deuterium.
 8. The processof claim 1, wherein the enamine of Formula (II), or a salt orisotopologue thereof, is an enamine of Formula (II-a):

or a salt or isotopologue thereof, wherein the enamine of Formula(II-a), or a salt or isotopologue thereof, is synthesized by reacting anitrile of Formula (IV):

or an isotopologue thereof, with CH₃SO₂CH₃ and n-BuLi.
 9. The process ofclaim 1, wherein the enamine of Formula (II), or a salt or isotopologuethereof, is an enamine of Formula (II-b):

or a salt or isotopologue thereof, wherein the enamine of Formula(II-b), or a salt or isotopologue thereof, is synthesized by reacting anitrile of Formula (IV):

or an isotopologue thereof, with CD₃SO₂CD₃ and n-BuLi.
 10. The processof claim 1, wherein the hydrogenation in step (a) occurs with hydrogengas.
 11. The process of claim 1, wherein the hydrogenation in step (a)occurs with deuterium gas.
 12. The process of claim 1, wherein thehydrogenation in step (a) occurs in a solvent containing exchangeableproton for proton-deuterium exchange.
 13. The process of claim 12,wherein the solvent containing exchangeable proton for proton-deuteriumexchange is 2,2,2-trifluoroethanol.
 14. The process of claim 1, whereinthe hydrogenation in step (a) occurs in a solvent containingexchangeable deuterium for proton-deuterium exchange.
 15. The process ofclaim 14, wherein the solvent containing exchangeable deuterium forproton-deuterium exchange is 2,2,2-trifluoroethanol-d¹.
 16. The processof claim 1, wherein the hydrogenation in step (a) occurs in a solventcontaining neither exchangeable proton nor exchangeable deuterium forproton-deuterium exchange.
 17. The process of claim 1, wherein the metalcatalyst is Rh(cod)₂OTf.
 18. The process of claim 1, wherein the chiralligand is (S,R)-t-Bu Josiphos.